Unlike some other cancer types, there are no single driving mutations that underpin the formation and metastasis of prostate cancer. Recent studies, however, have flagged a number of changes in the way gene expression is regulated in prostate cancer, making the epigenome a logical place to explore how prostate cancer acquires resistance to conventional therapies and turns into an incurable metastatic disease.

Two recent studies in Nature Genetics have made headway in understanding the epigenetic changes that underlie tumor progression to metastatic castration-resistant prostate cancer (mCRPC).1,2 One, for instance, suggested that prostate cancer metastasizes by activating a dormant epigenetic program from fetal development.

Such advances are useful not only in “understanding the development of the disease, which is scientifically really quite relevant, but also understanding, when our current therapies stop working, why do they stop working and hopefully, giving us ideas about how to change that situation,” said David Quigley, assistant professor in the department of urology at the University of California, San Francisco, and a coauthor of 1 of the studies.

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 The other research, published on July 20, 2020 (in which Dr Quigley did not participate), is based on an analysis of 268 prostate tissue samples representing different disease states, including normal prostate epithelium, localized prostate tumors, and metastases.1 The authors used a technique called ChIP sequencing to assess where key transcription factor proteins were binding to DNA to regulate gene expression, focusing their investigations on the androgen receptor.

Once activated by androgen, the androgen receptor enters the nucleus and binds to DNA at various sites, typically at regulatory sequences that function as enhancers, modulating the expression of distant genes.

In healthy adult prostate tissue, there’s a distinct pattern of sequences that are bound by androgen receptor proteins. However, when the researchers mapped the androgen receptor binding sites in cancer tissue, they noticed distinct differences that occurred with tumor formation as well as metastasis.

“There is a distinct and consistent set of brand-new binding sites that are unique to tumors, and then another set of about 15,000 that are unique to metastases,” noted Mark Pomerantz, MD, a medical oncologist at the Dana-Faber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, Massachusetts. “The gene regulatory programs systematically and very consistently change in the transition from localized prostate tumors to metastatic tumors.”