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.
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.”
Through comparisons with a large number of epigenomes of normal fetal and adult human tissue, Dr Pomerantz and his colleagues found that the epigenetic program activated in metastatic tissue was most similar to that activated in a cell line from the human urogenital sinus, the fetal structure that creates the prostate, and fetal tissue developmentally most related to the prostate. The findings suggest that localized prostate cancer metastasizes not by inventing a new mechanism, but by tapping into a developmental program used by its embryonic ancestors that allow it to migrate through the body and invade foreign tissue.
“It makes sense that the cancer cell will reach for that low-hanging fruit. Because just like an embryo, a cancer needs to have cells that . . . are able to travel and take up residence somewhere else,” Dr Pomerantz said.
Comparisons with breast cancer tissue suggested that this specific mechanism might be unique to prostate cancer, but Dr Pomerantz said he suspects that other cancers could also be exploiting latent developmental programs. In addition, he and his colleagues also found that the sequences encoding the prostate-specific regulatory elements harbored genetic variants associated with prostate cancer risk.
Further analyses suggested that the epigenetic machinery used in fetal development doesn’t entirely disappear, but that “traces” of this program remain long into adulthood, as evidenced by other transcription factors, FOXA1 and HOXB13, that linger around embryonic regulatory regions — as if they’re “poised” to reactivate latent developmental programs, Dr Pomerantz said.
“I think it’s an excellent approach to understanding . . . where do these [epigenetic] changes come from,” said Dr Quigley of the study. “It’s really consistent with the long-known relevance of developmental pathways in cancer.”
In a second study published on July 13, 2020, Dr Quigley and his colleagues focused on a specific kind of epigenetic alteration to DNA — methylation, which regulates gene expression by modifying the accessibility of DNA to transcription factors.2 They reported distinct differences in methylation between metastatic prostate cancer tissue, primary prostate cancer tissue, and benign human tissue.
Interestingly, they observed a distinct epigenomic-based subtype in 22% of 100 examined mCRPC samples. This was associated with hypermethylation as well as somatic mutations in genes such as TET1, DNMT3B, BRAF, and IDH1, which are key components of the methylation machinery. “[These genes] are associated with these global increases in methylation in the tumors in which they are mutated,” Dr Quigley said.
Dr Quigley said he expects such observations to spur the next cycle of functional studies that model such epigenetic changes in laboratory models and experimentally decipher what these epigenetic changes mean and how they alter prostate cancer cell function. Further down the road, that could pave the way for developing biomarkers based on epigenetic changes, or even novel therapies that tinker with the epigenetic machinery.
“As we explore the critical regulatory regions driving prostate cancer progression, we can begin to figure out which factors make these regulatory elements work, and which factors can be targeted and taken away to short-circuit these new regulatory programs,” Dr Pomerantz said. The ultimate question is, “can we rewire the epigenome and re-differentiate these cells to turn them back into the normal, benign tissue?”
- Pomerantz MM, Qiu X, Zhu Y et al. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet. 2020;52(8):790-799. doi:10.1038/s41588-020-0664-8
- Zhao SG, Chen WS, Li H et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52(8):778-789. doi:10.1038/s41588-020-0648-8
This article originally appeared on Cancer Therapy Advisor