Epigenetic mechanism of therapeutic resistance and potential of epigenetic therapeutics in chemorefractory prostate cancer

Prostate cancer is the second leading cause of cancer death among men in the United States. Depending upon the histopathological subtypes of prostate cancers, various therapeutic options, such as androgen deprivation therapy (ADT), androgen receptor signaling inhibitors (ARSI), immunotherapy, and chemotherapy, are available to treat prostate cancer. While these therapeutics are effective in the initial stages during treatments, the tumors subsequently develop resistance to these therapies. Despite all the progress made so far, therapeutic resistance remains a major challenge in the treatment of prostate cancer. Although various mechanisms have been reported for the resistance development in prostate cancer, altered expression of genes either directly or indirectly involved in drug response pathways is a common event. In addition to the genetic basis of gene regulation such as mutations and gene amplifications, epigenetic alterations involved in the aberrant expression of genes have frequently been shown to be associated not only with cancer initiation and progression but also with therapeutic resistance development. There are several review articles compiling reports on genetic mechanisms involved in therapeutic resistance in prostate cancer. However, epigenetic mechanisms for the therapeutic resistance development in prostate cancer have not yet been summarized in a review article. Therefore, the objective of this article is to compile various reports and provide a comprehensive review of the epigenetic aberrations, and aberrant expression of genes by epigenetic mechanisms involved in CRPCs and therapeutic resistance development in prostate cancer. Additionally, the potential of epigenetic-based therapeutics in the treatment of chemorefractory prostate cancer as evidenced by clinical trials has also been discussed.