Journal
SCIENCE ADVANCES
Volume 1, Issue 9, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.1500463
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Funding
- Department of Defense (DOD) Era of Hope Award [W81XWYH-11-1-0237]
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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-beta receptor (TGF-beta R) 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, andmutation of these sites in cell lines resulted in resistance to chemotherapy drugs. Furthermore, we showed that themethylation-dependent drug responsemechanism is distinct fromactivation of TGF-beta R signaling, becausemethylatedMED12 potently suppresses p21/WAF1 transcription. Cells defective inMED12 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.
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