ERα propelled aberrant global DNA hypermethylation by activating the DNMT1 gene to enhance anticancer drug resistance in human breast cancer

【作者】 司鑫鑫； 刘玥； 吕京澴； 丁海建； 张欣； 邵立培； 杨楠； 程禾； 孙鸾； 朱栋梁； 杨音； 李安迪； 韩晓； 孙玉洁；

【机构】 南京医科大学；

【摘要】 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.Breast cancer is an estrogen dependent cancer.In this study we systematically investigated whether and how estrogen receptor alpha(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 promoters of DNA transmethylases(DNMT1 and DNMT3 b) to activate DNMT1 and DNMT3 b genes,propelling aberrant global DNA methylation and enhancing the PTX resistance of breast cancer cells.In support of these observations,estrogen was proved to enhance multi-drug resistance of breast cancer cells by up-regulation of DNMT1 and DNMT3 b genes.Nevertheless,the aberrant global DNA hypermethylation was dominantly induced by ERα-activated-DNMT1,since DNMT1 over-expression significantly increased global DNA methylation and its deletion reversed the ERα-induced global DNA methylation.Altering DNMT3 b expression had no detectable effect on global DNA methylation.Consistently,our immunohistochemistry(IHC) analysis showed that the expression level of DNMT1 was positively correlated with ERα in 78 breast cancer tissue samples and negatively correlated with relapse-free survival(RFS) and distance metastasis-free survival(DMFS) of ERα-positive breast cancer patients.This study provides a novel perspective for understanding the mechanism underlying drug-resistance-facilitating aberrant DNA methylation in breast cancer and other estrogen dependent tumors and for development of new strategies to improve cancer chemotherapy.更多还原

【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.Breast cancer is an estrogen dependent cancer.In this study we systematically investigated whether and how estrogen receptor alpha(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 promoters of DNA transmethylases(DNMT1 and DNMT3 b) to activate DNMT1 and DNMT3 b genes,propelling aberrant global DNA methylation and enhancing the PTX resistance of breast cancer cells.In support of these observations,estrogen was proved to enhance multi-drug resistance of breast cancer cells by up-regulation of DNMT1 and DNMT3 b genes.Nevertheless,the aberrant global DNA hypermethylation was dominantly induced by ERα-activated-DNMT1,since DNMT1 over-expression significantly increased global DNA methylation and its deletion reversed the ERα-induced global DNA methylation.Altering DNMT3 b expression had no detectable effect on global DNA methylation.Consistently,our immunohistochemistry(IHC) analysis showed that the expression level of DNMT1 was positively correlated with ERα in 78 breast cancer tissue samples and negatively correlated with relapse-free survival(RFS) and distance metastasis-free survival(DMFS) of ERα-positive breast cancer patients.This study provides a novel perspective for understanding the mechanism underlying drug-resistance-facilitating aberrant DNA methylation in breast cancer and other estrogen dependent tumors and for development of new strategies to improve cancer chemotherapy.更多还原