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.

journal_name

Oncogene

journal_title

Oncogene

authors

Özeş AR,Miller DF,Özeş ON,Fang F,Liu Y,Matei D,Huang T,Nephew KP

doi

10.1038/onc.2016.75

subject

Has Abstract

pub_date

2016-10-13 00:00:00

pages

5350-5361

issue

41

eissn

0950-9232

issn

1476-5594

pii

onc201675

journal_volume

35

pub_type

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