title: 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.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Si
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ruochen
authors.initials: R
authors.lastname: Zang
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Erbao
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Shi
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ershao
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Lipei
authors.initials: L
authors.lastname: Shao
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Andi
authors.initials: A
authors.lastname: Li
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Beijing
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Luan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.|Collaborative Innovation Center for Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.|State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Cell Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C094335:H19 long non-coding RNA; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D062085:RNA, Long Noncoding; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D017239:Paclitaxel
keywords: apoptosis; breast cancer; chemoresistance; estrogen receptor; lncRNA H19