H19 Promotes EZH2-dependent Multidrug Resistance Through Epigenetical Silencing Of Pro-apoptotic Gene BIK In Breast Cancer Cells

Clinical drug resistance is a major cause of cancer treatment failure.Recent studies have shown that IncRNA plays an important role in of tumor chemotherapy resistance.LncRNA H19 is one of the earliest discovered IncRNA which plays an important role in the development of breast cancer,but the role in multidrug resistant breast cancer is unclear.This study was designed to determine the role of H19 and the underlying mechanisms of drug resistance in breast cancer.By using pre-established laboratory breast cancer resistant cell line MCF-7/PTX and ZR-75-1/PTX,We found that H19 expression was significantly increased in breast cancer resistant cells and that H19 induce multidrug resistance of breast cancer cells by inhibiting chemotherapeutic drug-induced apoptosis.lncRNA is known to regulate gene expression through multiple ways,including epigenetic,transcriptional and post-transcriptional level.H19 can bind to EZH2 and therefore inhibit the of expression of the target gene.EZH2,a histone H3 lysine 27 methyltransferase,acts as a transcriptional repressor involved in the regulation of gene silencing.It plays an important role in cancer development through promoting cell proliferation and migration,and inhibiting apoptosis.Our study showed that EZH2 and H19 were able to interact with each other and this interaction was further enhanced in resistant cells.Furthermore,H19 could bind EZH2 and direct it to the BIK gene promoter,catalyze trimethylation of H3K27,suppressing the gene expression,and thus promoting multidrug resistance by inhibiting breast cancer cell apoptosis.Estrogen receptor(ERa)has been known to promote breast cancer drug resistant cells.Oncomine online database analysis showed a strong positive correlation between ERa and H19,suggrsting the involvement of ERa in up-regulation of H19.Our results confirmed that alteration of ERa expression level by overexpression and knockdown experiments resulted in significant change in H19 expression level.Interference of H19 expression partially reversed ERa-mediated breast cancer drug resistance,indicating H19 was a downstream target gene of ERa.Altogether,our study revealed a new ERa-H19/EZH2-BIK pathway in breast cancer drug resistance and extended the understanding of the role of epigenetic regulation in cancer drug resistance.The new regulatory signaling axis may facilitate us to design new strategies to inprove the overall efficacy of chemotherapy of breast cancer.