title: ERα propelled aberrant global DNA hypermethylation by activating the DNMT1 gene to enhance anticancer drug resistance in human breast cancer cells.
abstract: 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.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Si
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Municipal Hospital, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu, China.
authors.forename: Jinghuan
authors.initials: J
authors.lastname: Lv
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Haijian
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Physiology and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Xin A
authors.initials: XA
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Lipei
authors.initials: L
authors.lastname: Shao
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: He
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Luan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Andi
authors.initials: A
authors.lastname: Li
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Collaborative Innovation Center for Cancer Medicine, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.|State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057890:Epigenomics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D017239:Paclitaxel
keywords: DNMT1; DNMT3b; ERα; breast cancer chemoresistance; global DNA hypermethylation