Epigenetics in prostate cancer treatment

Abstract

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men, and the progression of this disease results in fewer treatment options available to clinical patients. It highlights the vital necessity for discovering novel therapeutic approaches and expanding the current understanding of molecular mechanisms. Epigenetic alternations such as DNA methylation models and histone modifications have been associated as key drivers in the development and advancement of PCa. Several studies have been conducted and demonstrated that targeting these epigenetic enzymes or regulatory proteins has been strongly associated with the regulation of cancer cell growth. Due to the success rate of these therapeutic routes in pre-clinical settings, many drugs have now advanced to clinical testing, where efficacy will be measured. This review will discuss the role of epigenetic modifications in PCa development and its function in the progression of the disease to resistant forms and introduce therapeutic strategies that have demonstrated successful results as PCa treatment.

Prostate cancer genetic risk and associated aggressive disease in men of African ancestry

“…The gene-based analyses showed association between the genes H3C1, MBP, and MTG1 with PCa, and KLF5 with HRPCa. Modi cations to the H3 histone plays a key role in epigenetic regulation, and their relevance to PCa and treatment options have been reviewed elsewhere 52,53 . In this study, signi cant association of H3C1 to PCa suggests that differences in transcription may exist, and since the variant was only present in controls it may suggest a protective effect against PCa.…”

Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

“…Some KDM1A inhibitors being investigated in clinical trials to treat cancers are: ORY-1001, ORY-2001, GSK-2879552, IMG7289, INCB059872 and CC-90011 (chemical structure shown in Figure 5 ) ( 106 ). Other histone demethylases like KDM3A, KDM4B/KDM4C, KDM6A/KDM6B have also been associated with regulating the transcriptional activity of AR ( 107 – 110 ). Moreover, inhibitors simultaneously targeting KDM4 and KDM1 family enzymes have been developed and shown to be effective in inducing apoptosis of PCa and colon cancer cell lines ( 111 ).…”

“…However, recently it was shown that it also exhibits a separate activation function when it binds to the promoter region of AR and plays a role in AR signaling. It also acts as a co-activator of AR in CRPC [reviewed by Jones et al ( 110 )]. Recently, a study found that inhibition of EZH2 enhanced enzalutamide activity and could potential overcome enzalutamide resistance in CRPC.…”

Discovery of the First-in-Class G9a/GLP PROTAC Degrader

“…2,9−12 Overexpression of G9a has been reported in several cancer types, such as breast, 13,14 lung, 15,16 leukemia, 17 bladder, 18,19 colorectal, 20 and prostate. 21,22 G9a/GLP has also been implicated in diseases including sickle cell disease, 23 Prader−Willi syndrome, 24 and Alzheimer's disease. 25 In addition to G9a/GLP's wellestablished histone methyltransferase activity, studies have demonstrated that G9a/GLP has noncanonical oncogenic functions, such as methylating nonhistone proteins including HDAC1, DNMT1, and p53.…”

“…G9a (also known as euchromatic histone-lysine N -methyltransferase 2 (EHMT2)) and G9a-like protein (GLP, also known as EHMT1) are lysine methyltransferases that catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), transcriptionally repressive chromatin marks, and nonhistone proteins. − G9a and GLP, which share approximately 80% sequence homology in their catalytic SET domains, , play important roles in diverse cellular processes including cell development, differentiation, and hypoxia response. − When atypically expressed, the G9a/GLP axis promotes cancer progression, survival, and metastasis. ,− Overexpression of G9a has been reported in several cancer types, such as breast, , lung, , leukemia, bladder, , colorectal, and prostate. , G9a/GLP has also been implicated in diseases including sickle cell disease, Prader–Willi syndrome, and Alzheimer’s disease . In addition to G9a/GLP’s well-established histone methyltransferase activity, studies have demonstrated that G9a/GLP has noncanonical oncogenic functions, such as methylating nonhistone proteins including HDAC1, DNMT1, and p53. − Moreover, it has been shown that G9a/GLP have noncatalytic oncogenic activities by functioning as a coactivator independent of its catalytic domain. ,− For example, G9a positively regulates nuclear receptor gene expression by recruiting GRIP1, CARM1, and p300. ,, G9a is also recruited by Runx2 to downstream gene promoters to activate expression, , upregulates p21 via interaction with PCAF, and is a coactivator for a subset of p53 downstream genes, including pro-apoptotic Puma .…”