Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators : Asian Journal of Andrology

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Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

Takahashi, Sayuri1,2,; Takada, Ichiro1

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Asian Journal of Andrology 25(2):p 158-165, Mar–Apr 2023. | DOI: 10.4103/aja2022109
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Prostate cancer is a significant cause of mortality among men worldwide.1,2 The 5-year survival rate of men with prostate cancer who develop metastatic disease is only 29%.3 Androgen deprivation therapy (ADT) targeting the activity of the androgen receptor (AR; nuclear receptor subfamily 3 group C member 4 [NR3C4]) is an effective initial treatment for prostate cancer patients. AR is a member of the nuclear receptor gene superfamily, consisting of 48 genes in humans, and it acts as a ligand-dependent transcription factor in many tissues.4 Ligand-bound AR transcriptionally controls the expression of androgen target genes, such as prostate-specific antigen (PSA) and transmembrane protease serine 2 (TMPRSS2), in prostate cancer. There are many AR variants and mutations are reported to associate with prostate cancer progression.5 AR-null mutations in male mice lead to complete androgen insensitivity syndrome or the testicular feminization phenotype, demonstrating a fundamental role of androgen signaling in the differentiation and maintenance of male sexual characteristics.4

A high percentage of patients who undergo ADT become unresponsive to ADT after a few years. Dysfunction of the AR gene, such as gene mutations, deletion, and expression repression, is thought to cause the castration-resistant prostate cancer (CRPC) condition. Patients with metastatic CRPC have several treatment options, including taxanes, inhibitors of androgen signaling, and bone-targeted radiopharmaceutical agents;6 however, these therapies are associated with toxicity and a limited durable response.7 There is still an unmet clinical need to develop novel treatments for CRPC and to elucidate the molecular pathways that lead to this disease state.

In addition to the classical factors that regulate prostate cancer development such as AR, transforming growth factor-β (TGF-β),8 and interleukin-6 (IL-6),9 various transcriptional regulators and signaling pathways have been identified as driver genes of prostate cancer progression. Some inhibitors or activators of these regulators are being evaluated in clinical trials.10

Phosphatase and tensin homolog (PTEN)/phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is a major pathway regulating prostate cancer progression. PTEN deletion or point mutations causing inactivation have been identified in 20% of primary prostate cancer cases and approximately 35% of CPRC cases.11 Such PTEN mutations are associated with the activation of PI3K/AKT/mTOR signaling, and advanced prostate cancer patients with PTEN mutations have a poor prognosis. Several compounds targeting PI3K, AKT, or mTOR are being evaluated in clinical trials.10

The Hippo pathway and its downstream effectors, including the transcriptional co-activators Yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ), also promote prostate cancer development, hormone inhibition resistance, and metastasis.12 In prostate cancer, YAP acts as a transcriptional co-activator for AR, and TAZ is a potent regulator of epithelial-to-mesenchymal transition. Phosphorylated YAP/TAZ by the rapidly accelerated fibrosarcoma (RAF)/macrophage stimulating (MST)/large tumor suppressor kinase 1 (LATS1) pathway recruits 14-3-3 protein in the cytoplasm and leads to its degradation. Unphosphorylated YAP/TAZ resides in the nucleus, where it can associate with transcription factors to stimulate the transcription of genes involved in cell proliferation, cell cycle regulation, and apoptosis prevention. Oligonucleotide ISIS1532 inhibits C-raf and cell proliferation in vivo in mouse models of lung carcinoma.13 However, phase II clinical trials of ISIS1532 in patients with advanced prostate cancer showed no significant response, and the agent was withdrawn from further testing.14 Other therapies targeting the Hippo pathway will be required for patients with advanced prostate cancer.

Furthermore, the relationships between prostate cancer and other factors such as the microenvironment of immune cells,15,16 exercise-induced mytokines,17 and aging-dependent activation of senescence cells18 have been reported. As a microenvironmental factor, IL-23, which secreted from myeloid-derived suppressor cells, acts as a driver of CRPC in mice and humans.19 IL-23 increases the mRNA levels of the AR target genes NK3 homeobox 1 (Nkx3-1), probasin (Pbsn), and FK506-binding protein 5 (Fkbp5) in ADT-treated prostate cancer cells and AR-independent prostate cancer cells through the phosphor-signal transducer and activator of transcription 3 (pSTAT3)/retinoid-related orphan receptor gamma (RORγ) pathway. Another study showed that abiraterone, which is a selective cytochrome P450 family 17 (CYP17) inhibitor used to treat metastatic CRPC,20 is effective against CRPC in patients with a high level of IL-23-positive cell infiltration.21 Because IL-23-blocking antibodies are now used to treat autoimmune diseases,22 IL-23-positive cells may become a therapeutic target for CRPC, but further studies are required.

The canonical wingless-type MMTV integration site family (WNT)/β-catenin signaling pathway is an important regulator of prostate cancer development and metastasis.23 After canonical WNTs, such as WNT1 and WNT3A, bind to the frizzled (FZD) receptor, β-catenin that has accumulated in the cytoplasm enters the nucleus and acts as a transcriptional co-activator for the T-cell factor/lymphoid enhancer-binding factor 1 family of transcription factors, leading to the proliferation of prostate cancer cells. Conversely, inhibition of the WNT/β-catenin pathway suppresses prostate cancer cell proliferation. In addition, noncanonical WNT pathways, such as that involving WNT5A, also regulate prostate cancer progression and metastasis.

Moreover, transcriptional coregulators play pivotal roles in the regulation of prostate cancer proliferation by interacting with transcription factors that modulate mRNA expression.24 Transcriptional coregulators do not bind to specific DNA sequences but rather associate with transcription factors to regulate target gene transcription. This class of proteins includes histone modifiers, chromatin remodeling factors, and RNA polymerase regulators. Aberrant regulation of transcriptional coregulators through overexpression or mutation leads to cancer development.25,26 In particular, a recent review showed that alterations in chromatin remodeling factors play pivotal roles in CRPC development and metastasis.27

Previous research on the role of these signaling pathways and epigenetic regulators28 in prostate cancer has been described previously. In this review, we introduce recent findings regarding the role of the noncanonical WNT pathways and transcriptional coregulators.


The WNT family comprises 19 genes encoding secreted lipoglycoproteins that act as ligands to stimulate receptor-mediated signal transduction pathways in both vertebrates and invertebrates. WNT signaling pathways modulate cell proliferation, survival, behavior, and fate in both embryos and adults.29 There are two distinct WNT pathways: canonical and noncanonical. The canonical pathway regulates cell fate determination and is dependent on β-catenin. In contrast, the noncanonical WNT pathways are β-catenin-independent and in general control cell movement and tissue polarity. β-catenin acts as a coactivator for the AR in prostate cancer.30 In addition, there are multiple receptors for WNT ligands, such as FZD, LDL receptor-related protein (LRP)5/6, receptor tyrosine kinase-like orphan receptor (ROR)1/2 and receptor-like tyrosine kinase (RYK), and the internal signals activated by combinations of WNT ligands and receptors have different properties in prostate cancer.23

Furthermore, a role of noncanonical WNT signaling members (mainly WNT5A) in prostate cancer has been reported.31 WNT5A has been shown to promote prostate cancer cell migration and invasion, with its invasion activity dependent on the FZD2 and ROR2 WNT receptors.32 A mouse model of prostate cancer harboring a mutation conferring AR hypersensitivity (threonine 877 to alanine)33 developed a hypertrophic prostate with responses to both an androgen antagonist and estrogen. When these mutant mice were crossed with transgenic adenocarcinoma mouse prostate (TRAMP) mice, Wnt5a gene heterogeneous deletion abrogated tumor growth and suppressed the ligand-dependent transcriptional activity of AR.33 Recent genome-wide analyses showed that WNT5A is highly expressed in circulating prostate tumor cells,34 and several studies showed that it is a critical regulator of prostate cancer cell proliferation and invasion.

However, there is still controversy as to whether WNT5A acts as a promoter or suppressor of prostate cancer progression. In LNCaP cells, WNT5A overexpression leads to castration resistance in the bone niche with infiltrating macrophages through induction of C-C motif chemokine ligand 2 (CCL2) expression.35 In addition, prostate cancer patients with highly expressed WNT5A induce CCL2 mRNA through ROR2 which is a receptor for WNT5A.35 On the other hand, others showed that osteoblast-derived WNT5A in bone metastasis represses prostate cancer proliferation by suppressing WNT/β-catenin signaling.36 Prostate cancer patients without bone metastasis exhibit low β-catenin expression and high ROR2 expression. Conversely, prostate cancer patients with bone metastasis have high β-catenin expression and low ROR2 expression.36 Because stromal WNT5A enhances osteoclast differentiation through ROR2,37 WNT5A may play other roles in prostate cancer with bone metastasis. In PC-3 cells, FZD5 or RYK knockdown abrogated the ability of WNT5A to suppress cell proliferation and induce apoptosis. In prostate cancer patients, the levels of FZD5 and RYK were correlated with WNT5A expression and the Gleason score.38 Another group showed that stromal WNT5A expression was negatively correlated with high-grade prostate cancer but was not correlated with overall or cancer-specific survival.39 However, WNT/β-catenin signaling induces expression levels of ROR1, which is another receptor of WNT5A in prostate cancer.40 These studies implicate the complexity of crosstalk between WNT/β-catenin signaling and WNT5A signaling. These negative and positive effects of WNT5A in prostate cancer remain unclear. One hypothesis is that these effects may depend on both WNT5A and its membrane receptor. The expression levels of WNT5A pathway molecules or other factors may affect the treatment of CRPC.

Interestingly, the WNT5A-mimicking hexapeptide Foxy-5 shows different effects on DU145 (low WNT5A expression) and PC-3 (high WNT5A expression) cells in a xenograft mouse model.41 Foxy-5 inhibits cell invasion in DU145 cells, but not PC-3 cells. However, Foxy-5 did not affect tumor growth and apoptosis in a DU145 xenograft mouse model.41 These results suggest that the effect of WNT5A differs depending on the characteristics and genetic background of CRPC. Although Foxy-5 is undergoing a phase II clinical trial in colon cancer with low WNT5A expression (NCT03883802), the effect of Foxy-5 in prostate cancer may be limited. Further investigation and analysis of WNT5A pathway molecules in prostate cancer will be required.


Chromatin remodeling complexes contain multiple subunits, and adenosine triphosphate (ATP)-dependent chromatin remodelers mediate nucleosome dynamics.42 Several chromatin remodeling complexes are known, such as the SWI/SNF complexes,43 imitation switch (ISWI) complexes,44 inositol requiring mutant 80 (INO80) complex45 and chromatin organization domain (chromodomain) helicase DNA-binding (CHD) proteins, which are involved in cancer progression.46 These chromatin complexes and histone-modifying enzymes also regulate DNA repair and are critical regulators of prostate cancer progression.

In the SWI/SNF complex, Brahma and Brahma-related gene 1 (BRG1) has ATP-dependent nucleosome remodeling activities and associate with the acetylated lysine of histone H3. Recently, Xiao et al.47 clearly demonstrated the importance of the SWI/SNF complex in prostate cancer using a proteolysis-targeting chimera degrader of BRG1 and Brahma, AU-15330. Treatment with AU-15330 reduced the proliferation of LNCaP, VCaP, and 22Rv1 cells more than that of PTEN-deficient prostate cancer cells such as PC-3 and DU145 cells. Xenograft experiments using nude mice showed that combination treatment with AU-15330 and enzalutamide markedly reduced prostate cancer cell proliferation. AU-15330 treatment reduced the protein levels of AR, forkhead box A1 (FOXA1), ETS-related gene (ERG), and Myc.47

Ding et al.48 performed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated knockout of components of the SWI/SNF complex (Brg1, Jumonji domain containing 6 [Jmjd6] and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 [Smarce1]) in PTEN-deficient 22Rv1 cells. These knockout cells exhibited reduced proliferation. BRG1 is highly expressed in prostate cancer, and BRG1 knockdown reduced the proliferation of PTEN-deficient prostate cancer cells in a xenograft model and in Pten knockout mice. AKT phosphorylation or glycogen synthase kinase 3β (GSK3β) knockdown stabilizes BRG1 protein levels. BRG1 phosphorylated at S1417/1421 is ubiquitinated by F-Box and WD repeat domain containing 7 (FBXW7), thereby leading to BRG1 protein degradation.48

The core components of the SWI/SNF complex (BRG1, BRG1-associated factor 53B [BAF53B] and BRG1-associated factor 45B [BAF45B]) are highly expressed in neuroendocrine prostate cancer, and BRG1 associates with different proteins in neuroendocrine prostate cancer and adenocarcinoma prostate cancer.49 In neuroendocrine prostate cancer, BRG1 interactants were involved in chromatin regulation or DNA repairs such as BAF53B and BAF45B, but BRG1 in adenocarcinoma prostate cancer cells highly associates with homeobox B13 (HOXB13), which is involved in AR signaling.49 Prostate cancer patients with high BRG1 expression exhibit a low survival rate. In prostate cancer, the SWI/SNF complex associates with the nucleosome remodeling and deacetylase (NuRD) complex, which contains CHD4 and induces transcriptional repression.49 These studies demonstrate the importance of high BRG1 expression in enhancing prostate cancer cell proliferation. AU-15330 may become a new drug target for prostate cancer therapy.


The CHD family consists of nine members, CHD1–9, containing a chromodomain that binds specifically to modified histones and an SNF2-like ATP-dependent helicase domain that facilitates nucleosome mobilization.50 CHD proteins also exhibit ATPase-dependent chromatin remodeling through association with a methylated lysine of histone H3. The chromodomain was originally identified as a 37-amino acid region of homology shared by epigenetic repressors, heterochromatin protein 1 and Polycomb in Drosophila melanogaster. In addition, chromodomains have also been found in ATP-dependent chromatin remodeling factors, histone acetyltransferases, and histone methyltransferases.51 The binding ability of CHD chromodomains to modified histones differs, and this discrepancy is responsible for the diverse roles of CHD proteins.

CHD1 binds to histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 36 trimethylation (H3K36me3) and controls transcription elongation.52 Homozygous deletion of the CHD1 gene was frequently seen in prostate cancer patients and significantly associates with prostate cancer development.53 CHD1 loss causes global chromatin structure changes resulting in transcriptional changes.54 Such CHD1 loss in prostate cancer patients is associated with poor clinical response to antiandrogen therapy. There are also reported CHD1 mutations associated with metastatic CRPC.55,56 CHD1-knockout mice exhibit embryonic lethality at embryonic day (E) 5.5 due to growth retardation.57 Moreover, CHD1 is involved in cancer progression through regulation of nuclear factor-kappa B (NF-κB) target genes in PTEN-deficient prostate cancer.58 This raises the possibility of CHD1 as a new therapeutic target for prostate cancer. In addition to the role of CHD1 in CRPC, CHD1 alters AR binding sites from AR-half-site motif to HOXB13 motif in AR-positive prostate cancer cells with CHD1 deletion59 and abrogates anti-androgenic effects by inducing transcription factors such as the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1 [NR3C1]).60 These findings suggest the importance of CHD1 in prostate cancer development, and CHD1-specific inhibitors may provide a novel drug target for prostate cancer therapy.

CHD5 is a component of the NuRD complex and consists mainly of histone deacetylase (HDAC) 1/2, metastasis-associated (MTA), GATA zinc finger domain containing 2A (GATAD2A), RB binding protein 4/7 (RBBP4/7), methyl-CpG binding domain protein 2/3 (MBD2/3), and Mi-2, acting as transcriptional repressors.61 Among the CHD family members, CHD5 was first identified as a tumor suppressor frequently deleted in a variety of cancers.62 According to the copy number and targeted mutational analysis of 3508 exons from 577 metastatic prostate cancer-related genes, CHD5 mutations (R581S and A451V) are associated with metastatic prostate tumor development.63 However, CHD5 is reported to regulate transcriptional activation by binding to trimethylated histone H3 lysines.64 It has been suggested that CHD5 binds to the amino-terminal tail of unmodified histone H3 through the plant homeodomain of CHD5.65 Roles of CHD5 mutations in metastatic prostate tumor development are still under investigation.

CHD6 has been identified as a driver gene of CRPC.66 CHD6 also acts as an oxidative DNA damage response factor.67 Since oxidative DNA damage enhances prostate cancer progression,68 CHD6 may act as a prostate cancer driver gene through the DNA damage response.

CHD8 can bind to H3K4me2/3 and its expression in metastatic prostate cancer is increased in the nucleus.69 High expression of CHD8 is associated with a low survival rate in prostate cancer patients and the expression of the brother of the regulator of imprinted sites (BORIS), which is an antagonistic regulator of CHD8, and is inversely correlated with that of CHD8.69

These results suggest the importance of CHD proteins in prostate cancer progression. CHD inhibitors may offer new drug targets for prostate cancer.


Proteins of the bromodomain (BRD) adjacent to zinc finger domain (BAZ) family, which comprises four genes in humans (BAZ1A, BAZ1B, BAZ2A, and BAZ2B), have similar domain organization, including a plant homeodomain–BRD interaction module. BAZ1A was first identified in HeLa cell nuclear extracts as a factor that interacts with sucrose nonfermenting protein 2 homolog (SNF2H) to form a complex possessing ATP-dependent chromatin-remodeling activity.70 BAZ2A binds to acetylated K14 of histone H3 and acetylated K16 of H4 through its BRD.71 BAZ2A is located in the inactive enhancer region and suppresses transcription factor activity. Moreover, high expression levels of BAZ2A in prostate cancer patients significantly correlate with disease recurrence72. BAZ2A inhibitors (BAZ2A-ICR and GSK2801) abrogate PTEN-deficient prostate cancer progression.73 These inhibitors have potentials as agents for prostate cancer treatment, and further clinical trials will be needed.


Histone-modifying enzymes form the basis of epigenetics, and they modify histones through acetylation/deacetylation, methylation/demethylation, ADP-ribosylation, phosphorylation, or ubiquitination.42 One such enzyme is poly(ADP-ribose) polymerase (PARP). In particular, PARP inhibitor (Olaparib) treatment shows the longer progression-free survival on CRPC metastasis, in which one gene among breast cancer susceptibility gene 1 (BRCA1), BRCA2, or ATM serine/threonine kinase (ATM) is mutated and was confirmed in phase III clinical trials.74,75 PARP repairs single-strand DNA breaks through base excision repair pathways, and PARP inhibitors increase the number of single-strand breaks and promote cell death in prostate cancer.7 In addition, histone methyltransferases and demethylases play a pivotal role in prostate cancer progression. Recent studies suggest that these enzymes are also required for post-translational modifications of proteins other than histones.

Lysine demethylase 5B (KDM5B) is an H3K4me2/3 demethylase that represses transcriptional activity. KDM5B knockout in PTEN-deficient cells reduced prostate cancer cell proliferation. Kdm5b/Pten-knockout inhibited the PI3K/Akt pathway in mice.76 KDM5B directly binds to the phosphoinositide 3-kinase alpha (PIK3CA) gene promoter, and KDM5B knockout resulted in significant reductions in PIK3CA and phosphatidylinositol-3,4,5-triphosphate (PIP3) levels and a subsequent decrease in proliferation in human prostate cancer cells. KDM5B expression is upregulated in prostate cancer patients, and high expression is associated with poor survival.77 Although still under investigation, KDM5B is being proposed as a target for cancer therapy,78 and KDM5B selective inhibitors, such as GSK467, may become new therapeutic agents for prostate cancer.

The H3K9 demethylase Jumonji domain-containing protein 1A (JMJD1A; KDM3A) enhances the transcriptional activities of AR and c-Myc.79 JMJD1A is highly expressed in CRPC. JMJD1A is acetylated by p300 at K421, and acetylated JMJD1A interacts with bromodomain containing 4 (BRD4), which is a member of the bromodomain and extraterminal protein family that interacts with acetylated histones.80 K421 of JMJD1A is critical for ubiquitin-dependent degradation by STIP1 homology and U-box containing protein 1 (STUB1), and the association of JMJD1A with BRD4 protects against ubiquitin-dependent degradation. This JMJD1A–BRD4 interaction leads to high expression of JMJD1A, resulting in AR activation in CRPC.81

Lysine-specific histone demethylase 1 (LSD1; KDM1A) is a histone demethylase that contributes to transcriptional repression through H3K4me1/2 demethylation and transcriptional activation through H3K9me1/2 demethylation by transcription factors and other histone modifications. LSD1 enhances FOXA1 binding to chromatin by promoting demethylation of K270 of FOXA1 (in humans).82 It has been shown that the LSD1 inhibitor GSK2879552 causes growth inhibition of prostate cancer cells, including in xenograft experiments.82 Another LSD1 inhibitor, INCB059872, is undergoing a clinical trial in other cancer cell types.83

Lysine methyltransferase 2D (KMT2D; also called MLL2/4) is an H3K4 methyltransferase and its mutations are associated within metastatic CRPC.55,56 In Chinese prostate cancer patients, KMT2D expression levels correlate to poor prognosis.84 Inhibitors of KMT2D (compounds 1 and 16) reduce prostate cancer proliferation and migration.85 Although the effect of this inhibitor on other types of cancer cells has not been investigated, KMT2D may become a new drug target. Future reports on the therapeutic effect of this inhibitor are awaiting.

A recent study showed histone H3K9 methyltransferases play pivotal roles during the early phase of prostate cancer progression.86 The mRNA level of the H3K9 methyltransferase euchromatic histone lysine methyltransferase 1 (EHMT1) is highly induced after LNCaP cells acquire resistance to enzaltamide (an AR ligand). The mRNA levels of other H3K9 methyltransferases (EHMT2 and SET domain bifurcated histone lysine methyltransferase 1 [SETDB1]) are also induced during this phase. SETDB1 is a regulator of many types of cancers.87 In non-small and small lung cancer cell lines and primary tumors, gene amplification of SETDB1 is related to an increase of tumor growth and invasiveness.88 Such induction of H3K9 methyltransferases results in the expansion of heterochromatin regions.86 Thus, induction of H3K9 methyltransferases is necessary for inducing enzalutamide resistance in prostate cancer.

In a CRISPR/Cas9 knockout screen in parental hormone-dependent LNCaP cells and their hormone-refractory counterpart LNCaP-abl cells, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) was identified as a suppressed gene in LNCaP-abl cells.89 EZH2 is an H3K27 methyltransferase that was originally identified as the catalytic subunit of the polycomb repressive complex 2, which induces gene silencing. Interestingly, EZH2 inhibitors (GSK126 and EPZ-6438) that block EZH2 enzymatic activity markedly reduced the proliferation of CRPC cells. These compounds inhibit FOXA1 methylation and suppress the mRNA levels of DNA-damage-related genes. Thus, EZH2 inhibitors are potential candidates for CRPC therapies. Two EZH2 variants (rs7858903490 and rs230242791) are associated with increased prostate cancer risk.

SET domain-containing protein 2 (SETD2) is an H3K36 trimethylation enzyme that regulates transcription elongation and splicing.92 Mutations in SETD2 are prevalent in a variety of human tumors, most significantly in clear cell renal cell carcinoma and glioma.93 In prostate cancer, SETD2 methylates K735 of EZH2 and enhances its degradation.94 The level of H3K36 trimethylation is inversely correlated with that of EZH2-catalyzed H3K27 trimethylation. Low expression of SETD2 in prostate cancer patients is associated with a low survival rate. High Gleason score patients show low expression levels of SETD2.94 The expression levels of SETD2 and EZH2 are inversely correlated in prostate cancer. In SETD2-deficient cells, EZH2 expression and activity are increased, resulting in an increased H3K27me3 level and risk of metastasis. Mutated SETD2 (R1523H), observed in cancers, can no longer interact with EZH2.94 Moreover, SETD2 expression is regulated by 5’ adenosine monophosphate-activated protein kinase (AMPK) signaling. These results indicate that expression regulation or enzymatic inhibition of SETD2 is potential drug targets for prostate cancer. SETD2-selective inhibitors (EPZ-719,95 compound C13,96 and EZM041497) have been reported. Among them, compound C13 inhibits the proliferation of leukemia cell lines96 and EZM0414 inhibits the proliferation of multiple myeloma cells in xenograft model mice.97 Thus, these compounds may be a useful drug for prostate cancer, although EZH2 expression levels may be altered.

Disruptor of telomeric silencing 1-like (DOT1L) is a histone H3 lysine 79 (H3K79) methyltransferase and is highly expressed in prostate cancer patients. High expression of DOT1L is associated with a low survival rate.98 The DOT1L inhibitor (EPZ-5676) suppresses the proliferation of AR-positive prostate cancer cells and reduces AR protein expression. Both DOT1L-specific small hairpin RNA (shRNA) and EPZ-5676 reduce MYC mRNA expression. Moreover, DOT1L represses ubiquitin-dependent degradation of MYC and AR. Whether the methyltransferase activity of DOT1L is necessary for protein degradation remains unclear.98 The DOT1L inhibitor pinometostat is currently in a phase I clinical trial for treatment of acute myeloid leukemia.99


Histone acetylation and lysine methylation are the major histone modifications controlling gene transcription. Recent studies have shown the importance of arginine methylation. However, the association of histone arginine methylation with cancer progression has been poorly studied.100 Both arginine depletion strategies101 and arginine methyltransferase (PRMT) inhibitors102 are being tested in clinical trials as therapeutic strategies for cancer.

Arginine methylation is catalyzed by PRMT enzymes. Nine PRMTs (PRMT1–9) are present in mammalian genomes. Each PRMT isoform harbors the characteristic motifs of the seven-β-strand methyltransferase family, as well as additional ‘double E’ and ‘THW’ sequence motifs characteristic of the PRMT subfamily of methyltransferases. PRMTs catalyze three types of arginine methylation. Of these, monomethylation generates an intermediate in the formation of dimethylated arginine. PRMT1 and PRMT5 are the primary enzymes responsible for the asymmetric dimethylation of histone H4R3 and for symmetric dimethylation, respectively.

PRMT4 and PRMT 5 regulate transcriptional activity through histone arginine methylation. PRMT4 is a type I arginine methyltransferase that catalyzes monomethylation and asymmetric dimethylation of the R17 and R26 residues of histone H3103 and non-histone proteins such as RNA polymerase II.104 PRMT5 is a type II arginine methyltransferase that catalyzes symmetric dimethylation of arginine residues on histones H2–4 (H2AR3, H3R8, and H4R3). Clinical studies showed that PRMT4 and another PRMT, PRMT1, are upregulated early during prostate cancer progression. PRMT1 highly expresses in metastatic prostate cancer and high PRMT1 expression shows low survival rates.105 In particular, PRMT4 is highly expressed in hormone-naïve high-grade prostate cancer patients (prognostic grade group 3–5) and correlated with markers of cell cycle regulation, and both PRMT1 and PRMT4 are correlated with markers of epithelial-to-mesenchymal transition.106 Recently, pheophorbide a/b isolated from Foeniculum vulgare was identified as an inhibitor of PRMT4 and PRMT5, suppressing prostate cancer cell proliferation.107 These results suggest epigenetic regulation by pheophorbide a/b, in addition to its effect on G1/G0 phase arrest through reactive oxygen species induction and autophagy activation in PC-3 cells.108

Some of these epigenetic inhibitors are being evaluated in clinical trials as potential novel drug treatments for prostate cancer.109


Other types of transcriptional coregulators have been reported to have roles in prostate cancer. BRD9 is a lysine-acetylated histone H3-binding protein of the glioma tumor suppressor candidate region gene 1 protein (GLTSCR1)/GLTSCR1 like (GLTSCR1L)-BAF complex, a subtype of the SWI/SNF complex. High expression of BRD9 is associated with a low survival rate in prostate cancer patients. BRD9 interacts with BRD proteins (e.g., BRD2 and BDR4) to activate AR function.110

According to a database search, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is highly expressed in prostate cancer patients. PGC1A is a 91-kDa protein originally identified as a nuclear receptor coactivator that regulates lipid metabolism and long-chain fatty acid oxidation.111 PGC1A knockdown reduced the proliferation of LNCaP cells, and PGC1A regulated the expression of a vast number of genes.112

Rapid immunoprecipitation mass spectrometry of endogenous protein experiments113 in LNCaP cells identified enhanced at puberty 1 (EAP1/IRF2BPL) as a coactivator for AR.114 EAP1 enhances the transcriptional activity of AR through E3 ubiquitin ligase activity, and its ubiquitination substrates include AR and HDAC1. EAP1 is highly expressed in prostate cancer, and EAP1 knockdown reduces endogenous mRNA expression of AR target genes such as PSA and kallikrein-related peptidase 2 (KLK2).

Genome-wide CRISPR screening in LNCaP cells revealed that RNA processing factor heterogeneous nuclear ribonucleoprotein L (HnRNP-L), which controls alternative mRNA splicing, regulates prostate cancer cell proliferation.115 HnRNP-L is overexpressed in prostate cancer compared with other cancers. In prostate cancer, HnRNP-L knockdown inhibited cell proliferation, and its overexpression promoted cell proliferation and tumor growth, in part through interaction with endogenous p53 mRNA.116 These results suggest that HnRNP-L is a marker gene and therapeutic target for prostate cancer.


Here, we reviewed recent studies of regulators of noncanonical WNT5A signaling and transcriptional coregulators involved in prostate cancer progression, as summarized in Table 1 and 2. Some related compounds and antibodies have been evaluated in clinical trials as treatments for prostate cancer;10 therefore, we can expect novel drug treatments for prostate cancer patients in the near future. Recent studies have shown the importance of chromatin remodeling complexes in prostate cancer progression and metastasis. However, the binding regions of different chromatin complexes on the genome are not distinct, and the significance of the differences among chromatin remodeling complexes is unclear. Genome-wide analysis revealed that CRPC varies in its genomic background and epigenetic changes. Moreover, single-nucleotide polymorphisms (SNPs) are associated with prostate cancer development.55,117 Analysis of the relationship between identified SNPs and described factors will be a subject for future work. In summary, recent studies revealed the new roles of WNT signaling and transcriptional factors on prostate cancer. Individual genomic and epigenetic characteristics will be necessary for future therapeutic approaches for CRPC.

Table 1:
Recent findings regarding the role of WNT5A pathway in prostate cancer
Table 2:
Representative small compounds regulating transcriptional regulation in prostate cancer


ST conceived and designed this review, and revised the drafts. IT drafted the manuscript. Both authors read and approved the final manuscript.


Both authors declare no competing interests.


This review was supported by Grant-in-Aid for Scientific Research ([C] grant No. 22K09442).


1. Rebello RJ, Oing C, Knudsen KE, Loeb S, Johnson DC, et al. Prostate cancer. Nat Rev Dis Primers 2021;7:9
2. Siegel RL, Miller KD, Fuchs HE, Jemal A Cancer statistics 2022. CA Cancer J Clin 2022;72:7 33
3. Siegel RL, Miller KD, Jemal A Cancer statistics 2019. CA Cancer J Clin 2019;69:7 34
4. Matsumoto T, Sakari M, Okada M, Yokoyama A, Takahashi S, et al. The androgen receptor in health and disease. Annu Rev Physiol 2013;75:201 24
5. Labbe DP, Brown M Transcriptional regulation in prostate cancer. Cold Spring Harb Perspect Med 2018;8:a030437
6. de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med 2019;381:2506 18
7. Martin GA, Chen AH, Parikh K A novel use of olaparib for the treatment of metastatic castration-recurrent prostate cancer. Pharmacotherapy 2017;37:1406 14
8. Mirzaei S, Paskeh MD, Saghari Y, Zarrabi A, Hamblin MR, et al. Transforming growth factor-beta (TGF-beta) in prostate cancer:a dual function mediator?Int J Biol Macromol 2022;206:435 52
9. Culig Z Proinflammatory cytokine interleukin-6 in prostate carcinogenesis. Am J Clin Exp Urol 2014;2:231 8
10. He Y, Xu W, Xiao YT, Huang H, Gu D, et al. Targeting signaling pathways in prostate cancer:mechanisms and clinical trials. Signal Transduct Target Ther 2022;7:198
11. Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 2018;15:222 34
12. Salem O, Hansen CG The Hippo pathway in prostate cancer. Cells 2019;8:370
13. Monia BP, Sasmor H, Johnston JF, Freier SM, Lesnik EA, et al. Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C-raf kinase supports an antisense mechanism of action in vivo. Proc Natl Acad Sci U S A 1996;93:154814
14. Tolcher AW, Reyno L, Venner PM, Ernst SD, Moore M, et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res 2002;8:2530 5
15. Ferguson LP, Diaz E, Reya T The role of the microenvironment and immune system in regulating stem cell fate in cancer. Trends Cancer 2021;7:624 34
16. Kwon JT, Bryant RJ, Parkes EE The tumor microenvironment and immune responses in prostate cancer patients. Endocr Relat Cancer 2021;28:T95– 107
17. Kim JS, Galvao DA, Newton RU, Gray E, Taaffe DR Exercise-induced myokines and their effect on prostate cancer. Nat Rev Urol 2021;18:519 42
18. Fiard G, Stavrinides V, Chambers ES, Heavey S, Freeman A, et al. Cellular senescence as a possible link between prostate diseases of the ageing male. Nat Rev Urol 2021;18:597 610
19. Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 2018;559:363 9
20. Hoy SM Abiraterone acetate:a review of its use in patients with metastatic castration-resistant prostate cancer. Drugs 2013;73:2077 91
21. Liu Z, Zhang JY, Yang YJ, Chang K, Wang QF, et al. High IL-23+ cells infiltration correlates with worse clinical outcomes and abiraterone effectiveness in patients with prostate cancer. Asian J Androl 2022;24:147 53
22. Grossberg LB, Papamichael K, Cheifetz AS Review article:emerging drug therapies in inflammatory bowel disease. Aliment Pharmacol Ther 2022;55:789 804
23. Murillo-Garzon V, Kypta R WNT signalling in prostate cancer. Nat Rev Urol 2017;14:683 96
24. Rosenfeld MG, Lunyak VV, Glass CK Sensors and signals:a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 2006;20:1405 28
25. McKenna NJ, Evans RM, O'Malley BW Nuclear receptor signaling:a home for nuclear receptor and coregulator signaling research. Nucl Recept Signal 2014;12:e006
26. Jafari H, Hussain S, Campbell MJ Nuclear receptor coregulators in hormone-dependent cancers. Cancers (Basel) 2022;14:2402
27. Clapier CR, Iwasa J, Cairns BR, Peterson CL Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol 2017;18:407 22
28. Liao Y, Xu K Epigenetic regulation of prostate cancer:the theories and the clinical implications. Asian J Androl 2019;21:279 90
29. Rim EY, Clevers H, Nusse R The Wnt pathway:from signaling mechanisms to synthetic modulators. Annu Rev Biochem 2022;91:571 98
30. Chen SY, Wulf G, Zhou XZ, Rubin MA, Lu KP, et al. Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. Mol Cell Biol 2006;26:929 39
31. Fisher RR, Pleskow HM, Bedingfield K, Miyamoto DT Noncanonical Wnt as a prognostic marker in prostate cancer:"you can't always get what you Wnt". Expert Rev Mol Diagn 2020;20:245 54
32. Yamamoto H, Oue N, Sato A, Hasegawa Y, Yamamoto H, et al. Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. Oncogene 2010;29:2036 46
33. Takahashi S, Watanabe T, Okada M, Inoue K, Ueda T, et al. Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer. Proc Natl Acad Sci U S A 2011;108:4938 43
34. Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 2015;349:1351 6
35. Lee GT, Kwon SJ, Kim J, Kwon YS, Lee N, et al. WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages. Br J Cancer 2018;118:670 8
36. Ren D, Dai Y, Yang Q, Zhang X, Guo W, et al. Wnt5a induces and maintains prostate cancer cells dormancy in bone. J Exp Med 2019;216:428 49
37. Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 2012;18:405 12
38. Thiele S, Zimmer A, Gobel A, Rachner TD, Rother S, et al. Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget 2018;9:27293 304
39. Kisel W, Conrad S, Borkowetz A, Furesi G, Fussel S, et al. High stroma-derived WNT5A is an indicator for low-risk prostate cancer. FEBS Open Bio 2021;11:1186 94
40. Ma F, Arai S, Wang K, Calagua C, Yuan AR, et al. Autocrine canonical Wnt signaling primes noncanonical signaling through ROR1 in metastatic castration-resistant prostate cancer. Cancer Res 2022;82:1518 33
41. Canesin G, Evans-Axelsson S, Hellsten R, Krzyzanowska A, Prasad CP, et al. Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model. PLoS One 2017;12:e0184418
42. Zhao S, Allis CD, Wang GG The language of chromatin modification in human cancers. Nat Rev Cancer 2021;21:413 30
43. Hartley A, Leung HY, Ahmad I Targeting the BAF complex in advanced prostate cancer. Expert Opin Drug Discov 2021;16:173 81
44. Goodwin LR, Picketts DJ The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. Mol Cell Neurosci 2018;87:55 64
45. Poli J, Gasser SM, Papamichos-Chronakis M The INO80 remodeller in transcription, replication and repair. Philos Trans R Soc Lond B Biol Sci 2017;372:20160290
46. Mills AA The chromodomain helicase DNA-binding chromatin remodelers:family traits that protect from and promote cancer. Cold Spring Harb Perspect Med 2017;7:a026450
47. Xiao L, Parolia A, Qiao Y, Bawa P, Eyunni S, et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature 2022;601:434 9
48. Ding Y, Li N, Dong B, Guo W, Wei H, et al. Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer. J Clin Invest 2019;129:759 73
49. Cyrta J, Augspach A, De Filippo MR, Prandi D, Thienger P, et al. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity. Nat Commun 2020;11:5549
50. Marfella CG, Imbalzano AN The Chd family of chromatin remodelers. Mutat Res 2007;618:30 40
51. Eissenberg JC Molecular biology of the chromo domain:an ancient chromatin module comes of age. Gene 2001;275:19 29
52. Lee Y, Park D, Iyer VR The ATP-dependent chromatin remodeler Chd1 is recruited by transcription elongation factors and maintains H3K4m|ne3/H3K36me3 domains at actively transcribed and spliced genes. Nucleic Acids Res 2017;45:7180 90
53. Liu W, Lindberg J, Sui G, Luo J, Egevad L, et al. Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene 2012;31:3939 48
54. Zhang Z, Zhou C, Li X, Barnes SD, Deng S, et al. Loss of CHD1 promotes heterogeneous mechanisms of resistance to AR-targeted therapy via chromatin dysregulation. Cancer Cell 2020;37:584 98 e11
55. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;162:454
56. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A 2019;116:11428 36
57. Guzman-Ayala M, Sachs M, Koh FM, Onodera C, Bulut-Karslioglu A, et al. Chd1 is essential for the high transcriptional output and rapid growth of the mouse epiblast. Development 2015;142:118 27
58. Zhao D, Lu X, Wang G, Lan Z, Liao W, et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 2017;542:484 8
59. Augello MA, Liu D, Deonarine LD, Robinson BD, Huang D, et al. CHD1 loss alters AR binding at lineage-specific enhancers and modulates distinct transcriptional programs to drive prostate tumorigenesis. Cancer Cell 2019;35:603 17 e8
60. Zhang D, Hu Q, Liu X, Ji Y, Chao HP, et al. Intron retention is a hallmark and spliceosome represents a therapeutic vulnerability in aggressive prostate cancer. Nat Commun 2020;11:2089
61. Quan J, Yusufzai T The tumor suppressor chromodomain helicase DNA-binding protein 5 (CHD5) remodels nucleosomes by unwrapping. J Biol Chem 2014;289:20717 26
62. Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, et al. CHD5 is a tumor suppressor at human 1p36. Cell 2007;128:459 75
63. Robbins CM, Tembe WA, Baker A, Sinari S, Moses TY, et al. Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome Res 2011;21:47 55
64. Paul S, Kuo A, Schalch T, Vogel H, Joshua-Tor L, et al. Chd5 requires PHD-mediated histone 3 binding for tumor suppression. Cell Rep 2013;3:92 102
65. Oliver SS, Musselman CA, Srinivasan R, Svaren JP, Kutateladze TG, et al. Multivalent recognition of histone tails by the PHD fingers of CHD5. Biochemistry 2012;51:6534 44
66. Zhang W, Wang T, Wang Y, Zhu F, Shi H, et al. Intratumor heterogeneity and clonal evolution revealed in castration-resistant prostate cancer by longitudinal genomic analysis. Transl Oncol 2022;16:101311
67. Moore S, Berger ND, Luijsterburg MS, Piett CG, Stanley FK, et al. The CHD6 chromatin remodeler is an oxidative DNA damage response factor. Nat Commun 2019;10:241
68. Schiewer MJ, Knudsen KE DNA damage response in prostate cancer. Cold Spring Harb Perspect Med 2019;9:a030486
69. Damaschke NA, Yang B, Blute ML Jr, Lin CP, Huang W, et al. Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer. Neoplasia 2014;16:1018 27
70. Bochar DA, Savard J, Wang W, Lafleur DW, Moore P, et al. A family of chromatin remodeling factors related to Williams syndrome transcription factor. Proc Natl Acad Sci U S A 2000;97:1038 43
71. Tallant C, Valentini E, Fedorov O, Overvoorde L, Ferguson FM, et al. Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC. Structure 2015;23:80 92
72. Gu L, Frommel SC, Oakes CC, Simon R, Grupp K, et al. BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nat Genet 2015;47:22 30
73. Pena-Hernandez R, Aprigliano R, Carina Frommel S, Pietrzak K, Steiger S, et al. BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells. EMBO Rep 2021;22:e53014
74. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020;382:2091 102
75. LeVee A, Lin CY, Posadas E, Figlin R, Bhowmick NA, et al. Clinical utility of olaparib in the treatment of metastatic castration-resistant prostate cancer:a review of current evidence and patient selection. Onco Targets Ther 2021;14:4819 32
76. Li G, Kanagasabai T, Lu W, Zou MR, Zhang SM, et al. KDM5B is essential for the hyperactivation of PI3K/AKT signaling in prostate tumorigenesis. Cancer Res 2020;80:4633 43
77. Liu B, Kumar R, Chao HP, Mehmood R, Ji Y, et al. Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer. Oncotarget 2020;11:4243 52
78. Jose A, Shenoy GG, Sunil Rodrigues G, Kumar NA, Munisamy M, et al. Histone demethylase KDM5B as a therapeutic target for cancer therapy. Cancers (Basel) 2020;12:2121
79. Fan L, Peng G, Sahgal N, Fazli L, Gleave M, et al. Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival. Oncogene 2016;35:2441 52
80. Davies A, Zoubeidi A, Selth LA The epigenetic and transcriptional landscape of neuroendocrine prostate cancer. Endocr Relat Cancer 2020;27:R35– 50
81. Xu S, Fan L, Jeon HY, Zhang F, Cui X, et al. p300-mediated acetylation of histone demethylase JMJD1A prevents its degradation by ubiquitin ligase STUB1 and enhances its activity in prostate cancer. Cancer Res 2020;80:3074 87
82. Gao S, Chen S, Han D, Wang Z, Li M, et al. Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer. Nat Genet 2020;52:1011 7
83. Fang Y, Liao G, Yu B LSD1/KDM1A inhibitors in clinical trials:advances and prospects. J Hematol Oncol 2019;12:129
84. Lv S, Ji L, Chen B, Liu S, Lei C, et al. Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4. Oncogene 2018;37:1354 68
85. Yu Q, Liao Z, Liu D, Xie W, Liu Z, et al. Small molecule inhibitors of the prostate cancer target KMT2D. Biochem Biophys Res Commun 2020;533:540 7
86. Baratchian M, Tiwari R, Khalighi S, Chakravarthy A, Yuan W, et al. H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer. Proc Natl Acad Sci U S A 2022;119:e2114324119
87. Strepkos D, Markouli M, Klonou A, Papavassiliou AG, Piperi C Histone methyltransferase SETDB1:a common denominator of tumorigenesis with therapeutic potential. Cancer Res 2021;81:525 34
88. Rodriguez-Paredes M, Martinez de Paz A, Simo-Riudalbas L, Sayols S, Moutinho C, et al. Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene 2014;33:2807 13
89. Liao Y, Chen CH, Xiao T, de la Pena Avalos B, Dray EV, et al. Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress. Proc Natl Acad Sci U S A 2022;119:e2105898119
90. Raspin K, FitzGerald LM, Marthick JR, Field MA, Malley RC, et al. A rare variant in EZH2 is associated with prostate cancer risk. Int J Cancer 2021;149:1089 99
91. Ling Z, You Z, Hu L, Zhang L, Wang Y, et al. Effects of four single nucleotide polymorphisms of EZH2 on cancer risk:a systematic review and meta-analysis. Onco Targets Ther 2018;11:851 65
92. Edmunds JW, Mahadevan LC, Clayton AL Dynamic histone H3 methylation during gene induction:HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J 2008;27:406 20
93. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma Nature 2013;499:43 9
94. Yuan H, Han Y, Wang X, Li N, Liu Q, et al. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell 2020;38:350 65 e7
95. Lampe JW, Alford JS, Boriak-Sjodin PA, Brach D, Cosmopoulos K, et al. Discovery of a first-in-class inhibitor of the histone methyltransferase SETD2 suitable for preclinical studies. ACS Med Chem Lett 2021;12:1539 45
96. Bajusz D, Bognar Z, Ebner J, Grebien F, Keseru GM Discovery of a non-nucleoside SETD2 methyltransferase inhibitor against acute myeloid leukemia. Int J Mol Sci 2021;22:10055
97. Alford JS, Lampe JW, Brach D, Chesworth R, Cosmopoulos K, et al. Conformational-design-driven discovery of EZM0414:a selective, potent SETD2 inhibitor for clinical studies. ACS Med Chem Lett 2022;13:1137 43
98. Vatapalli R, Sagar V, Rodriguez Y, Zhao JC, Unno K, et al. Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer. Nat Commun 2020;11:4153
99. Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood 2018;131:2661 9
100. Jarrold J, Davies CC PRMTs and arginine methylation:cancer's best-kept secret?. Trends Mol Med 2019;25:993 1009
101. Zou S, Wang X, Liu P, Ke C, Xu S Arginine metabolism and deprivation in cancer therapy. Biomed Pharmacother 2019;118:109210
102. Li X, Wang C, Jiang H, Luo C A patent review of arginine methyltransferase inhibitors (|y2010-2018). Expert Opin Ther Pat 2019;29:97 114
103. Schurter BT, Koh SS, Chen D, Bunick GJ, Harp JM, et al. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry 2001;40:5747 56
104. Sims RJ 3rd, Rojas LA, Beck DB, Bonasio R, Schuller R, et al. The C-terminal domain of RNA polymerase II is modified by site-specific methylation. Science 2011;332:99 103
105. Tang S, Sethunath V, Metaferia NY, Nogueira MF, Gallant DS, et al. A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer. Cell Rep 2022;38:110417
106. Grypari IM, Logotheti S, Zolota V, Troncoso P, Efstathiou E, et al. The protein arginine methyltransferases (PRMTs) PRMT1 and CARM1 as candidate epigenetic drivers in prostate cancer progression. Medicine (Baltimore) 2021;100:e27094
107. Wang Z, Xiong L, Xiong Q Purification and identification of natural inhibitors of protein arginine methyltransferases from plants. Mol Cell Biol 2022;42:e0052321
108. Xu DD, Lam HM, Hoeven R, Xu CB, Leung AW, et al. Photodynamic therapy induced cell death of hormone insensitive prostate cancer PC-3 cells with autophagic characteristics. Photodiagnosis Photodyn Ther 2013;10:278 87
109. Lopez J, Anazco-Guenkova AM, Monteagudo-Garcia O, Blanco S Epigenetic and epitranscriptomic control in prostate cancer. Genes (Basel) 2022;13:378
110. Alpsoy A, Utturkar SM, Carter BC, Dhiman A, Torregrosa-Allen SE, et al. BRD9 is a critical regulator of androgen receptor signaling and prostate cancer progression. Cancer Res 2021;81:820 33
111. Lin J, Handschin C, Spiegelman BM Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005;1:361 70
112. Siddappa M, Wani SA, Long MD, Leach DA, Mathe EA, et al. Identification of transcription factor co-regulators that drive prostate cancer progression. Sci Rep 2020;10:20332
113. Mohammed H, Taylor C, Brown GD, Papachristou EK, Carroll JS, et al. Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for analysis of chromatin complexes. Nat Protoc 2016;11:316 26
114. Yokoyama A, Kouketsu T, Otsubo Y, Noro E, Sawatsubashi S, et al. Identification and functional characterization of a novel androgen receptor coregulator, EAP1. J Endocr Soc 2021;5:bvab150
115. Fei T, Chen Y, Xiao T, Li W, Cato L, et al. Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proc Natl Acad Sci U S A 2017;114:E5207– 15
116. Zhou X, Li Q, He J, Zhong L, Shu F, et al. HnRNP-L promotes prostate cancer progression by enhancing cell cycling and inhibiting apoptosis. Oncotarget 2017;8:19342 53
117. Allemailem KS, Almatroudi A, Alrumaihi F, Makki Almansour N, Aldakheel FM, et al. Single nucleotide polymorphisms (SNPs) in prostate cancer:its implications in diagnostics and therapeutics. Am J Transl Res 2021;13:3868 89

chromatin remodeling; histone-modifying enzymes; prostate cancer; WNT5A

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