ERα propelled aberrant global DNA hypermethylation by activating the DNMT1 gene to enhance anticancer drug resistance in human breast cancer cells
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Xinxin Si1,5,*, Yue Liu1,5,*, Jinghuan Lv6, Haijian Ding1,5, Xin A. Zhang4, Lipei Shao1,5, Nan Yang1, He Cheng1,5, Luan Sun1,5, Dongliang Zhu5, Yin Yang1,5, Andi Li1,5, Xiao Han1, Yujie Sun1,2,3,5
1Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
2Collaborative Innovation Center for Cancer Medicine, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
3State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
4Department of Physiology and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
5Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China
6Department of Pathology, Municipal Hospital, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu, China
*These authors have contributed equally to this work
Yujie Sun, e-mail: [email protected]
Keywords: ERα, DNMT1, DNMT3b, global DNA hypermethylation, breast cancer chemoresistance
Received: July 31, 2015 Accepted: February 16, 2016 Published: March 12, 2016
Drug-induced aberrant DNA methylation is the first identified epigenetic marker involved in chemotherapy resistance. Understanding how the aberrant DNA methylation is acquired would impact cancer treatment in theory and practice. In this study we systematically investigated whether and how ERα propelled aberrant global DNA hypermethylation in the context of breast cancer drug resistance. Our data demonstrated that anticancer drug paclitaxel (PTX) augmented ERα binding to the DNMT1 and DNMT3b promoters to activate DNMT1 and DNMT3b genes, enhancing the PTX resistance of breast cancer cells. In support of these observations, estrogen enhanced multi-drug resistance of breast cancer cells by up-regulation of DNMT1 and DNMT3b genes. Nevertheless, the aberrant global DNA hypermethylation was dominantly induced by ERα-activated-DNMT1, since DNMT1 over-expression significantly increased global DNA methylation and DNMT1 knockdown reversed the ERα-induced global DNA methylation. Altering DNMT3b expression had no detectable effect on global DNA methylation. Consistently, the expression level of DNMT1 was positively correlated with ERα in 78 breast cancer tissue samples shown by our immunohistochemistry (IHC) analysis and negatively correlated with relapse-free survival (RFS) and distance metastasis-free survival (DMFS) of ERα-positive breast cancer patients. This study provides a new perspective for understanding the mechanism underlying drug-resistance-facilitating aberrant DNA methylation in breast cancer and other estrogen dependent tumors.
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