Homo sapiens Raw sequence reads

Long non-coding RNAs (lncRNAs) play diverse functional roles in cancer. The HOX transcript antisense RNA (HOTAIR) lncRNA in particular is associated with metastasis, proliferation, and epithelial to mesenchymal transition in various tumor types. In this study, we find that upregulation of HOTAIR induced ovarian cancer (OC) cisplatin (CDDP) resistance in vitro and in vivo. HOTAIR expression levels were significantly increased in recurrent vs. primary OC as well as in platinum-resistant vs sensitive tumors. To investigate the role of HOTAIR during DNA damage response (DDR) induced by CDDP, we monitored double-strand breaks (DSBs) using ?-H2AX and found that the expression of HOTAIR allows for a sustained activation of DDR after CDDP treatment. We demonstrate that ectopic expression of HOTAIR induces activation of the transcription factor nuclear factor kappa B (NF-?B) during DDR as well as expression of MMP-9 and IL-6, key NF-?B target genes. We show that HOTAIR regulates NF-?B activation by decreasing NF-?B inhibitor alpha (I?-Ba) protein levels and establish that by inducing prolonged NF-?B activation and expression of NF-?B target genes during DNA damage, HOTAIR plays a critical role in OC cellular senescence and CDDP sensitivity. Our findings suggest that HOTAIR-NF-?B signaling drives a positive-feedback loop cascade during DDR and contributes to cellular senescence and chemotherapy resistance in ovarian and other cancers.