LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway

// Qiong-Ni Zhu 1 , Guo Wang 1 , Ying Guo 1 , Yan Peng 1 , Rui Zhang 1 , Jun-Li Deng 1 , Zhi-Xing Li 1 and Yuan-Shan Zhu 1, 2 1 Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Central South University, Changsha, P. R. China 2 Department of Medicine, Weill Cornell Medical College, New York, NY, USA Correspondence to: Yuan-Shan Zhu, email: yuz2002@med.cornell.edu Guo Wang, email: 207082@csu.edu.cn Keywords: chemoresistance, lncRNA H19, CUL4A, ABCB1, breast cancer Received: February 10, 2017      Accepted: September 04, 2017      Published: September 21, 2017 ABSTRACT Development of chemoresistance is a persistent problem during cancer treatment. Long non-coding RNAs (LncRNAs) are currently emerging as an integral functional component of the human genome and as critical regulators of cancer development and progression. In the present study, we investigated the role and molecular mechanism of H19 lncRNA in chemoresistance development by using doxorubicin (Dox) resistance in breast cancer cells as a model system. H19 lncRNA expression was significantly increased in anthracycline-treated and Dox-resistant MCF-7 breast cancer cells. This H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 lncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel. Furthermore, gene expression profiling analysis revealed that a total of 192 genes were associated with H19-mediated Dox resistance. These genes were enriched in multiple KEGG pathways that are related to chemoresistance. Using genetic and pharmacological approaches, we demonstrated that MDR1 and MRP4 were major effectors of H19-regulated Dox resistance in breast cancer cells as MDR1 and MRP4 expression was markedly elevated in Dox-resistant cells while dramatically reduced when H19 was knocked down. Moreover, we found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 lncRNA to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy. These data suggest that H19 lncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19 - CUL4A - ABCB1 / MDR1 pathway.