title: MED12 methylation by CARM1 sensitizes human breast cancer cells to chemotherapy drugs.
abstract: The RNA polymerase II mediator complex subunit 12 (MED12) is frequently mutated in human cancers, and loss of MED12 has been shown to induce drug resistance through activation of transforming growth factor-β receptor (TGF-βR) signaling. We identified MED12 as a substrate for coactivator-associated arginine methyltransferase 1 (CARM1). Not only are the expression levels of CARM1 and MED12 positively correlated, but their high expression also predicts better prognosis in human breast cancers after chemotherapy. MED12 was methylated at R1862 and R1912 by CARM1, and mutation of these sites in cell lines resulted in resistance to chemotherapy drugs. Furthermore, we showed that the methylation-dependent drug response mechanism is distinct from activation of TGF-βR signaling, because 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 chemotherapy drugs in human cancers.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zeng
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. ; Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Zibo
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Boyer
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. ; Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Bian
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
keywords: CARM1; RNA polymerase II mediator complex; breast cancer; chemotherapy; methylation