Protein Holds Promise for Prostate Cancer Treatment
Gene-slicing protein could serve as target for new prostate cancer treatments.
-- by Alexia Severson
Researchers have discovered an unexpected role for a gene-slicing protein in prostate cancer, which holds promise for prostate cancer treatments, according to a new study published in Science.
These gene-slicing proteins are known as epigenetic regulators, which influence gene expression and cancer progression. Researchers found that one such regulator, called EZH2, plays a role in castration-resistant prostate cancer, a particularly aggressive form of the disease in which new tumors form even after the testicles have been removed to deplete androgens.
Previous studies have shown that EZH2 switches off the expression of tumor-suppressing genes. However, new research reveals that the protein plays quite a different role in this form of prostate cancer, working with the androgen receptor to activate the expression of certain other genes.
Study authors hypothesize that targeting EZH2's activation function, while sparing its other activities, may serve as an effective strategy against metastatic, hormone-refractory prostate cancer.
The Expert Take
Previous studies have shown that though these tumors do not depend on gonadal androgens, or male hormones, they often continue to depend on the androgen receptor, said Myles Brown, M.D., study author and Professor of Medicine at Harvard Medical School.
“While in some cases this is explained by the ability of the tumor to make its own androgens, in other advanced cases it appears that the androgen receptor is acting without androgens,” he said. “We wanted to understand what factors allow the androgen receptor to function without androgens in castration-resistant prostate cancer.”
In previous work, Brown said his team found that under these conditions the androgen receptor (AR), which maintains the normal development of the prostate, was reprogrammed to regulate a distinct set of genes that promote the growth of the tumor.
“Because of this reprogramming of androgen receptor function, we focused on epigenetic regulators as potential players, and in particular EZH2, which had previously been shown to be increased in castration-resistant prostate cancer,” he said.
Source and Method
Brown and his colleagues conducted experiments using cell lines and tissue samples from cancer patients. The team used the LNCaP cell line as a model of androgen-dependent prostate cancer and LNCaPabl (abl), its androgen-independent derivative, to study EZH2 function in the progression of prostate cancer to castration-resistant prostate cancer (CRPC).
They also used chromatin immunoprecipitation sequencing to determine the gene activation function of EZH2 and conducted a motif analysis to determine how EZH2 might be targeted to solo peaks.
According to the American Cancer Society, prostate cancer is the most common cancer in American men, second to skin cancer, and about one man in six will be diagnosed with prostate cancer during his lifetime. The American Cancer Society also estimates that, in 2012, about 241,740 new cases of prostate cancer will be diagnosed and about 28,170 men will die from the disease.
Based on these statistics, it is easy to see why a better understanding of prostate cancer and improved methods of treatment are so important. This research could be the key to developing a drug that specifically inhibits the gene activation function of EZH2 and effectively treats castration-resistant prostate cancer. And according to Brown, this study also brings light to a previously under-appreciated aspect of EZH2 function involving gene activation rather than repression.
As with most cancers, a wide range of research has been conducted on prostate cancer, but few have focused specifically on the function of EZH2 in castration-resistant prostate cancer.
In a study published in the Journal of Clinical Oncology in 2006, researchers linked strong EZH2 expression with increased tumor cell proliferation in four types of cancer: cutaneous melanoma, cancers of the endometrium, breast cancer, and prostate cancer. Their study also revealed independent prognostic importance of EZH2 in cancer of the endometrium and prostate.
In another study published in PNAS in 2003, researchers inspired by the role of EZH2 in prostate cancer, investigated the functional role of EZH2 in cancer cell invasion and breast cancer progression. Based on a tissue microarray analysis, which included 917 samples from 280 patients, researchers found that EZH2 protein levels were strongly associated with breast cancer aggressiveness.
In a different approach, researchers identified the proteins that mediate tumor progression among patients who relapse with aggressive prostate cancer even after treatment in a study published in Cancer Research in 2006. In this study, multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors, including EZH2. Researchers concluded that “enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.”