LncRNA H19 confers chemoresistance in ERα-positive breast cancer through epigenetic silencing of the pro-apoptotic gene BIK.

Abstract

Breast cancer is a common malignancy in women. Acquisition of drug resistance is one of the main obstacles encountered in breast cancer therapy. Long non-coding RNA (lncRNA) has been demonstrated to play vital roles in both development and tumorigenesis. However, the relationship between lncRNAs and the development of chemoresistance is not well established. In the present study, the high expression of lncRNA H19 was identified as a powerful factor associated with paclitaxel (PTX) resistance in ERα-positive breast cancer cells, but not in ERα-negative breast cancer cells. LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIK and NOXA. H19 was further confirmed to suppress the promoter activity of BIK by recruiting EZH2 and by trimethylating the histone H3 at lysine 27. Interestingly, our data showed that lncRNA H19 was one of the downstream target molecules of ERα. Altered ERα expression may therefore change H19 levels to modulate the apoptosis response to chemotherapy in breast cancer cells. Our data suggest that the ERα-H19-BIK signaling axis plays an important role in promoting chemoresistance.

• Authors: Xinxin Si, Ruochen Zang, Erbao Zhang, Yue Liu, Xiao Shi, Ershao Zhang, Lipei Shao, Andi Li, Nan Yang, Xiao Han, Beijing Pan, Zhihong Zhang, Luan Sun, Yujie Sun
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 49 Pg. 81452-81462 (Dec 06 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27845892 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BIK protein, human
• ESR1 protein, human
• Estrogen Receptor alpha
• H19 long non-coding RNA
• Membrane Proteins
• Mitochondrial Proteins
• PMAIP1 protein, human
• Proto-Oncogene Proteins c-bcl-2
• RNA, Long Noncoding
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Paclitaxel

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• DNA Methylation
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (genetics)
• Enhancer of Zeste Homolog 2 Protein (genetics, metabolism)
• Epigenesis, Genetic
• Estrogen Receptor alpha (drug effects, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Membrane Proteins (genetics, metabolism)
• Mitochondrial Proteins
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA Interference
• RNA, Long Noncoding (genetics, metabolism)
• Signal Transduction
• Transcription, Genetic
• Transfection