Abstract
Abstract Chemotherapy continues to be an important treatment to reduce the risk of metastatic breast cancer recurrence. However, many tumors relapse due to the development of multidrug resistance, the mechanisms of which remain poorly understood. Therefore, there is a pressing need to elucidate mechanisms of resistance and discover a sensitive biomarker that could predict patient response to chemotherapeutic drugs. We discovered that chemosensitivity can be predicted by methylation of a mediator of RNA polymerase II transcription subunit 12 (MED12) by coactivator associated arginine methyltransferase 1 (CARM1). MED12 is frequently mutated in human cancers, and loss of MED12 has been shown to induce drug resistance through activation of TGF-βR signaling. We showed that MED12 is a novel substrate of CARM1. Not only are the expression levels of CARM1 and MED12 positively correlated but their high expression predicts better prognosis in human breast cancers after chemotherapy. MED12 was primarily methylated at R1862 by CARM1, and mutation of this site in cell lines resulted in resistance to chemotherapy drugs (e.g. 5-FU). A change in chemosensitivity by altering the methylation status of a single protein in breast cancer cells is unprecedented. Mechanistically, we showed that the methylation-dependent drug response mechanism is distinct from activation of TGF-βR signaling. Further, we found that methylated MED12 potently suppresses p21/WAF1 transcription. Cells defective in MED12 methylation have up-regulated p21 protein, which correlates with poor prognosis in breast cancer patients treated with chemotherapy. Collectively this study identifies MED12-methylation as a sensor for predicting response to commonly used chemo-drugs in human cancers. Citation Format: Wang Lu, Hao Zeng, Qiang Wang, Zibo Zhao, Thomas G. Boyer, Xiuwu Bian, Wei Xu. MED12 methylation by CARM1 sensitizes human breast cancer cells to chemotherapy drugs. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR12.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
