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

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

doi:10.18632/oncotarget.13263

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

Oncotarget. 2016 Dec 6;7(49):81452-81462. doi: 10.18632/oncotarget.13263.

Authors

Xinxin Si^{1

2}, Ruochen Zang^{1

2}, Erbao Zhang³, Yue Liu^{1

2}, Xiao Shi^{1

2}, Ershao Zhang^{1

2}, Lipei Shao^{1

2}, Andi Li^{1

2}, Nan Yang^{1

3}, Xiao Han^{1

3}, Beijing Pan⁴, Zhihong Zhang⁴, Luan Sun^{1

2}, Yujie Sun^{1

5

6

2}

Affiliations

¹ Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
² Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
³ Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
⁴ Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
⁵ Collaborative Innovation Center for Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.
⁶ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

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.

Keywords: apoptosis; breast cancer; chemoresistance; estrogen receptor; lncRNA H19.

MeSH terms

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

Substances

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