Researchers at the University of Adelaide in Australia have found that Grainyhead-like protein 2, called GRHL2, plays a dual role in prostate cancer by both promoting and preventing cancer growth. It also was found to be a regulator of the androgen receptor (AR), which is essential for the development of prostate cancer.
While being key to the functioning of AR, GRHL2 also inhibits cellular mechanisms that are necessary for prostate cancer cells to spread to other organs.
The study, “Novel androgen receptor co-regulator GRHL2 exerts both oncogenic and anti-metastatic functions in prostate cancer,” published in the journal Cancer Research, provides new insight into the underlying mechanisms of aggressive castration-resistant prostate cancer and could lead to new treatment approaches.
“We desperately need better therapies for this common killer of men. Our study provides important new insights into the biology of prostate cancer, which we aim to translate to new treatment strategies in the future,” Luke Selth, PhD, senior author of the study, said in a news release.
The researchers found that GRHL2 was expressed in several models of prostate cancer, including drug-resistant tumors. In addition, its activity was essential for maintaining AR expression, promoting its activity, and inducing cancer cell growth.
“The protein encoded by [GRHL2] appears to be vital for the function of the key driver of prostate cancer growth, the androgen receptor: it not only maintains levels of the androgen receptor, but also enhances its activity,” said Selth, who is a senior research fellow at the University of Adelaide’s Dame Roma Mitchell Cancer Research Laboratories and a member of the Freemasons Foundation Center for Men’s Health.
“Interestingly, while we think this novel function connected with the androgen receptor means that GRHL2 will generally be a ‘bad player’ in prostate cancer, we also found evidence that the GRHL2 protein could be a ‘good player’ in certain contexts by inhibiting the spread of the cancer,” Selth added.
The team found that inhibition of GRHL2 would induce prostate cancer cells to acquire biological features that would allow them to migrate and invade other organs. This suggests that while GRHL2 is expressed, the cells may grow via the activation of AR signals, but growth will be confined to the site of origin.
“While targeting GRHL2 could disable the AR signaling axis at multiple levels, it may concomitantly enhance the metastatic capacity of the tumor. As such, if strategies to inhibit GRHL2 were developed, their application in [prostate cancer] would require careful consideration,” the researchers wrote.
While the researchers recommend caution when targeting GRHL2, the findings are still significant because they describe a new regulator of the androgen receptor. As a result, the study was recently highlighted in the journal Nature Reviews Urology, in an article titled, “Prostate cancer: New AR co-regulator with dichotomous functions,” written by Clemens Thomas, PhD, senior editor of the journal.
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