BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype. Issue 11 (10th May 2019)

• Record Type: Journal Article
• Authors: Gorodetska, Ielizaveta; Lukiyanchuk, Vasyl; Peitzsch, Claudia; Kozeretska, Iryna; Dubrovska, Anna
• Is Part Of: International journal of cancer. Volume 145:Issue 11(2019)
• Page Start: 2974
• Page End: 2985
• Publication Date: 2019-05-10
• Subjects: BRCA1 -- EZH2 -- cancer stem cells -- prostate cancer -- DZNeP; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32323
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Prostate cancer (PCa) 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 nonstem‐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 dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2‐dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2‐mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa 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 an increase of aldehyde dehydrogenase (ALDH)‐positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3‐Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo . 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. Abstract : What's new? 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, leading to metastatic disease. Among the known critical epigenetic regulators of prostate cancer progression is EZH2, whose overexpression results in histone methylation‐driven tumor cell de‐differentiation. The present study demonstrates that EZH2 tightly cooperates with genome caretaker BRCA1 in the regulation of the phenotype and properties of prostate cancer stem cells, and that targeting these mechanisms may be a promising strategy for cancer treatment.