title: NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer.
abstract: The transcription factor nuclear factor kappa B (NF-κB) and the long non-coding RNA (lncRNA) HOTAIR (HOX transcript antisense RNA) have diverse functional roles in cancer. In this study, we show that upregulation of HOTAIR induced platinum resistance in ovarian cancer, and increased HOTAIR levels were observed in recurrent platinum-resistant ovarian tumors vs primary ovarian tumors. To investigate the role of HOTAIR during DNA damage induced by platinum, we monitored double-strand breaks and show that HOTAIR expression results in sustained activation of DNA damage response (DDR) after platinum treatment. We demonstrate that ectopic expression of HOTAIR induces NF-κB activation during DDR and interleukin-6 and interleukin-6 expression, both key NF-κB target genes. We show that HOTAIR regulates activation of NF-κB by decreasing Iκ-Bα (NF-κB inhibitor) and establish that by inducing prolonged NF-κB activation and expression of NF-κB target genes during DNA damage, HOTAIR has a critical role in cellular senescence and platinum sensitivity. Our findings suggest that an NF-κB-HOTAIR axis drives a positive-feedback loop cascade during DDR and contributes to cellular senescence and chemotherapy resistance in ovarian and other cancers.
authors.affiliation: Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Özeş
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Miller
authors.affiliation: Department of Medical Biology and Genetics, Akdeniz University, Antalya, Turkey.
authors.forename: O N
authors.initials: ON
authors.lastname: Özeş
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA.
authors.forename: F
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Indianapolis, IN, USA.|Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.|Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Matei
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.affiliation: Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, USA.|Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA.|Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.|Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Nephew
mesh_terms: D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; C561566:HOTAIR long untranslated RNA, human; D016328:NF-kappa B; D062085:RNA, Long Noncoding; D035602:Transcriptional Elongation Factors; D010984:Platinum