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) play 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 after platinum treatment. We demonstrate that ectopic expression of HOTAIR induces NF-κB activation during DNA damage response and MMP-9 and IL-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 plays a critical role in cellular senescence and platinum sensitivity. Our findings suggest that a NF-κB-HOTAIR axis drives a positive-feedback loop cascade during DNA damage response and contributes to cellular senescence and chemotherapy resistance in ovarian and other cancers.

Long non-coding RNAs in anti-cancer drug resistance

“…For instance, DNA is the key target of traditional chemotherapy drugs such as platinum, and cancer cells tend to be more resistant to platinum as a result of abnormal DNA damage repair activation [28, 29]. A latest study has observed that NF-κB/HOTAIR have interaction in DNA damage response in development of chemoresistance [30]. Accordingly, specific inhibition of DNA repair is believed to improve the efficacy of chemotherapeutics.…”

“…The ectopic expression of HOTAIR could persistently repair DNA damage attributed by platinum, and it activated NF-κB signaling. It is suggested that NF-κB/HOTAIR crosslinking contributed to chemoresistance in ovarian cancers [30]. …”

Role of lncRNAs in Cellular Aging

“…Furthermore, they demonstrated the presence of a positive-feedback loop that induces HOTAIR. This activates DDR and sustains NF-κB expression (115). Recently, Yoon et al reported a function of lncRNA HOTAIR as a scaffold for ubiquitin-mediated proteolysis in posttranslational control (116).…”

Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma

“…STAT3 promotes the transcription of lin-28, a post-transcriptional inhibitor of Let-7 miRNA biogenesis, while NF-κB was recently shown to activate the transcription of DICER. 87,101 However, it is still unclear whether STAT3/NF-κB physically interacts with the players of the miRNA biogenesis pathway. The second key question is what are the long non-coding RNAs that are transcriptionally controlled by NF-κB/STAT3?…”

“…Given the recent study demonstrating the activation of the NF-κB pathway by HOTAIR in ovarian cancer chemo resistance, it is tempting to speculate a similar mechanistic link between NF-κB and HOTAIR in ESCC. 87 In addition to the upstream regulation of NF-κB by lncRNAs, the study by Liu et al 88 profiled the non-coding interacting partners of this complex in cancer. This led to the identification of NF-κB interacting lncRNA (NKILA) which is upregulated by NF-κB, binds to NF-κB/IκB complex directly inhibiting IKK induced phosphorylation and activation of NF-κB pathway.…”