BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Prostate cancer is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell Transition between a stem- and non-stem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the Polycomb Repressive Complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells de-differentiation. Previous studies demonstrated that Tumor suppressor BRCA1 (breast cancer 1) is a negative regulator of PRC2-dependent H3K27 methylation and that loss of BRCA1 induces population of breast cancer stem cells (CSCs) and enhances aggressiveness of breast tumors. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate CSC population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are co-regulated in patients’ tumors and prostate cancer cell lines and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to enrichment of ALDH (aldehyde dehydrogenase) positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein, whereas treatment with a global histone methylation regulator DZNeP (3-Deazaneplanocin A) abrogates this regulation. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.