The deletion of a gene that normally promotes healthy cell division in the prostate encourages the growth of cancer in the gland, according to a new study by Weill Cornell Medicine investigators. The findings, published March 28 in Cancer Cell, suggest that the gene, once deleted, helps to promote tumorous growth.
Scientists knew that the gene, called chromodomain helicase DNA binding protein 1 or CHD1, was often deleted in prostate cancer cells, just like tumor-suppressor genes often are, said senior study author Dr. Christopher Barbieri, an associate professor of urology at Weill Cornell Medicine. “However, scientists did not know how and why CHD1 might be acting as a tumor suppressor,” he said.
“The interesting aspect of CHD1 deletion is that it seems to only occur in tumors that develop from the prostate,” said lead author Dr. Michael Augello, a post-doctoral fellow and Prostate Cancer Foundation Young Investigator in Dr. Barbieri’s lab. “This is unusual and suggests that CHD1 might have functions which are unique to prostate cells, which help to limit tumor formation.”
About 15 percent of men with prostate cancer have a CHD1 deletion in their tumors.
Typically, CHD1 helps regulate the positioning of nucleosomes, which are balls of protein that strands of DNA wrap around. “The DNA winds around them like beads on a string,” said Dr. Barbieri, who is also a member of the Sandra and Edward Meyer Cancer Center and the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine, and a urologist at NewYork-Presbyterian/Weill Cornell Medical Center. The function of CHD1 is to move the nucleosomes around on this string, making the DNA more or less accessible to molecules that are involved in turning genes on or off, called transcription factors.
In the study, Dr. Barbieri and his research team discovered that when CHD1 is present in prostate cells, it works with a transcription factor called the androgen receptor (AR), to turn on genes that are critical for normal functions of prostate tissue. When CHD1 is absent, however, the androgen receptor activates genes that promote cancer. “CHD1 appears to help AR turn on genes needed for prostate function,” Dr. Augello said. Without CHD1, AR has trouble regulating these programs, which helps to promote cancer growth.”
“AR has a dual role,” Dr. Barbieri added. “It’s important for a normal prostate, but it can also drive cancer.”
For their study, the investigators deleted the CHD1 gene in mice, which led to the growth of prostate cancer tumors. They also studied human prostate cancer cell lines in which the gene was deleted and confirmed their findings about the effect of CHD1 deletion on androgen receptors by analyzing data from a large number of human prostate tumors.
“Our study is one of the critical first steps in understanding the mechanisms by which the androgen receptor gets hijacked from promoting normal prostate function and turns toward promoting cancer,” Dr. Barbieri said.
He and his research team are now working on finding medications that can target the process of CHD1 deletion and the subsequent hijacking of androgen-receptors that drives prostate malignancies. “One of the big questions we have is whether the process is reversible,” he said. “Can we flip it back so the androgen receptor may cause the cancer to slow down and stop growing?”
This work was funded in part by the Prostate Cancer Foundation. “These important findings improve the understanding of how normal prostate cells can be transformed into cancer,” said Dr. Howard Soule, executive vice president and chief science officer of the Prostate Cancer Foundation. “The Prostate Cancer Foundation is proud to have supported this work through funding to Drs. Barbieri and Augello, which will accelerate discovery of new treatments for men with lethal forms of this disease.”
Additional funding sources include grants from the National Cancer Institute: WCM SPORE in Prostate Cancer, P50CA211024-01, K08CA187417-01, R37CA215040; a Urology Care Foundation Rising Star in Urology Research Award; Damon Runyon Cancer Research Foundation MetLife Foundation Family Clinical Investigator Award; Department of Defense Postdoctoral Fellowship; Prostate Cancer Foundation Young Investigator Award; the Dutch Cancer Society/ Alpe d’HuZes; and The Movember Foundation.