Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy

Abstract

Prostate cancer (PCa) is the most prevalent urological cancer that affects aging men in South Africa, and mechanisms underlying prostate tumorigenesis remain elusive. Research advancements in the field of PCa and epigenetics have allowed for the identification of specific alterations that occur beyond genetics but are still critically important in the pathogenesis of tumorigenesis. Anomalous epigenetic changes associated with PCa include histone modifications, DNA methylation, and noncoding miRNA. These mechanisms regulate and silence hundreds of target genes including some which are key components of cellular signalling pathways that, when perturbed, promote tumorigenesis. Elucidation of mechanisms underlying epigenetic alterations and the manner in which these mechanisms interact in regulating gene transcription in PCa are an unmet necessity that may lead to novel chemotherapeutic approaches. This will, therefore, aid in developing combination therapies that will target multiple epigenetic pathways, which can be used in conjunction with the current conventional PCa treatment.

Figure 1

Anterior whole body ¹⁷⁷Lu-PSMA scan of a 72-year-old patient with metastasised castration-resistant prostate cancer. This demonstrates normal biodistribution in the nasal region, salivary glands, liver, and spleen gastrointestinal and urinary system, with multiple PSMA-avid metastases in the prostate bed, clavicle, sternum, clavicle, vertebrae, iliac bone, and femora. An excellent response to therapy was observed after 3 cycles of ¹⁷⁷Lu-PSMA-RLT with decrease in serum PSA level (from 63 to 4.25 ng/mL).

Figure 2

Risk factors associated with the development of prostate cancer. PCa risk factors can be categorised as nonmodifiable (e.g., old age, ethnicity/race, and familial hereditary) and modifiable (diet and environmental/occupational factors).

Figure 3

Epigenetic mechanisms and therapy in advanced prostate cancer. Prostate cancer follows aberrant epigenetic alterations that are associated with perturbed cellular processes that are critical in tumorigenesis. In normal cell, CpG islands are protected from DNA methylation and deacetylation whereas a prostate cancer cell is characterised by tumour growth, differentiation, resistance, and metastasis resulting from aberrant DNA methylation and deacetylation. AR: androgen receptor; BET: bromodomain and extraterminal; CpG: cytosine-phosphate-guanine island; DNMTs: DNA methyltransferases; DOT1L: DOT1-like histone H3K79 methyltransferase; EZH2: enhancer of zeste 1; HDACs: histone deacetylases; DNMTs: DNA methyltransferase inhibitors; HDACs: histone deacetylase inhibitors.