Prostate Cells Undergo Epigenetic "Reprogramming" in Tumorigenesis
Cancerous prostate cells have had the androgen receptor transcription factor cistrome epigenetically ‘”reprogrammed’” to different binding sites.
In a breakthrough in the understanding of how prostate cancer originates, researchers have demonstrated that extensive epigenetic reprogramming of the androgen receptor (AR) transcription factor cistrome drives malignant growth of cancer cells.1
Activation of the AR is critical for cell growth and tumor progression in the prostate. Disrupting androgen metabolism affects prostate cancer occurrence, and depleting the AR ligand has been at the core of traditional prostate therapies. But until now, researchers had not identified precisely which cofactors were responsible for tumorigenesis.
Using human prostate tissue, a team led by Matthew Freedman, MD, and Mark Pomerantz, MD, of the Dana-Farber Cancer Institute in Boston, MA, identified a key set of AR binding sites that are consistently reprogrammed in tumors.
They selected sites that had “significantly elevated binding intensities across multiple tumor specimens” from different patients and compared these to normal tissue. They found that cistrome was binding to a different set of sites in cancerous tissue than in normal cells.
“This was a different approach,” said Dr. Pomerantz in an interview with Cancer Therapy Advisor. “We weren't studying the genetic code of cancer patients, but in a sense studying the epigenetic code. Sequencing studies in prostate cancer have not revealed many recurring genetic mutations. But we've known for generations that prostate cancer is an epigenetic disease. What has been unknown is exactly where on the DNA the AR, as a transcription factor, sits down to enact its program.”
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They identified 2 transcription factor binding motifs that were significantly enriched at AR binding sites in cancerous tissue. These were forkhead transcription factor FOXA1, and HOXB13. A rare genetic variant of HOXB13, G84E, is associated with a more than tenfold increased risk of prostate cancer.2