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

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INVITED REVIEW

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

Takahashi, Sayuri1,2,; Takada, Ichiro1

Author Information

1Department of Urology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

2Department of Urology, The Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Correspondence: Dr. S Takahashi ([email protected])

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Asian Journal of Andrology 25(2):p 158-165, Mar–Apr 2023. | DOI: 10.4103/aja2022109
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Abstract

INTRODUCTION

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 ROLE OF NONCANONICAL WNT PATHWAYS IN PROSTATE CANCER

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.

THE ROLE OF THE SWITCH/SUCROSE NONFERMENTABLE (SWI/SNF) COMPLEX IN PROSTATE CANCER

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 ROLE OF CHD PROTEINS IN PROSTATE CANCER

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.

OTHER CHROMATIN REMODELING COMPLEXES

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 METHYLTRANSFERASES/DEMETHYLASES IN PROSTATE CANCER

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

THE ROLE OF ARGININE METHYLTRANSFERASES IN PROSTATE CANCER

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 TRANSCRIPTIONAL COREGULATORS

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.

CONCLUSION AND FURTHER PERSPECTIVES

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.

T1
Table 1:
Recent findings regarding the role of WNT5A pathway in prostate cancer
T2
Table 2:
Representative small compounds regulating transcriptional regulation in prostate cancer

AUTHOR CONTRIBUTIONS

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

COMPETING INTERESTS

Both authors declare no competing interests.

ACKNOWLEDGMENTS

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

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Keywords:

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

Copyright: © The Author(s)(2023)