Recent Advances in Epigenetic Biomarkers and Epigenetic Targeting in Prostate Cancer

Abstract

Context: In addition to genetic alterations, epigenetic alterations play a crucial role during prostate cancer progression. A better understanding of the epigenetic factors that promote prostate cancer progression may lead to the design of rational therapeutic strategies to target prostate cancer more effectively.

Objective: To systematically review recent literature on the role of epigenetic factors in prostate cancer and highlight key preclinical and translational data with epigenetic therapies.

Evidence acquisition: We performed a systemic literature search in PubMed. At the request of the editors, we limited our search to articles published between January 2015 and August 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Clinical trials targeting epigenetic factors were retrieved from clinicaltrials.gov.

Evidence synthesis: We retrieved 1451 articles, and 62 were finally selected for review. Twelve additional foundational studies outside this time frame were also included. Findings from both preclinical and clinical studies were reviewed and summarized. We also discuss 12 ongoing clinical studies with epigenetic targeted therapies.

Conclusions: Epigenetic mechanisms impact prostate cancer progression. Understanding the role of specific epigenetic factors is critical to determine how we may improve prostate cancer treatment and modulate resistance to standard therapies. Recent preclinical studies and ongoing or completed clinical studies with epigenetic therapies provide a useful roadmap for how to best deploy epigenetic therapies clinically to target prostate cancer.

Patient summary: Epigenetics is a process by which gene expression is regulated without changes in the DNA sequence itself. Oftentimes, epigenetic changes influence cellular behavior and contribute to cancer development or progression. Understanding how epigenetic changes occur in prostate cancer is the first step toward therapeutic targeting in patients. Importantly, laboratory-based studies and recently completed and ongoing clinical trials suggest that drugs targeting epigenetic factors are promising. More work is necessary to determine whether this class of drugs will add to our existing treatment arsenal in prostate cancer.

Keywords: BET bromodomain; Chromatin; DNA methylation; DNA methyltransferase; Epigenetics; Histone acetyltransferase; Histone deacetylase; Histone demethylase; Histone methyltransferase; Prostate cancer; Ten-Eleven Translocation.

Fig. 1 –

Overview of histone or DNA modifiers implicated in prostate cancer. Key factors that modulate or recognize epigenetic marks in prostate cancer are shown. Although this figure is not exhaustive, the best studied factors previously implicated in prostate cancer are depicted. Those that are reviewed in this manuscript are indicated in bold. Factors that are upregulated in prostate cancer are shown in red, and downregulated factors are shown in green. These factors can be classified broadly into histone modifiers (histone methyltransferases [HMTs], histone acetyltransferases [HATs], bromodomain and extraterminal [BET] chromatin readers, histone deacetylases [HDACs], and histone demethylases [HDMs]) or DNA modifiers (DNA methyltransferases [DNMTs] and Ten-Eleven Translocation [TETs]) based on their substrate. Further, the factors are classified as writers, readers, or erasers based on their biochemical activity. The epigenetic marks modulated by these factors are being explored as potential biomarkers. Finally, drugs targeting many of these factors have been developed or are in development.

Fig. 2 –

Consort diagram depicting the literature selection and filtering process. The articles from the search results as described in the evidence acquisition section were aggregated and screened by a two-step screening process. A final list of 62 articles was selected for review. Twelve additional foundational articles were also included.