Long Noncoding RNAHITTERSProtects Oral Squamous Cell Carcinoma Cells from Endoplasmic Reticulum Stress-Induced Apoptosis via Promoting MRE11-RAD50-NBS1 Complex Formation

Recent studies have proven that long noncoding RNAs (lncRNAs) exhibit regulatory functions of both DNA damage response (DDR) and endoplasmic reticulum (ER) stress. Herein, ER stress-induced lncRNA transcriptomic changes are reported in human oral squamous cell carcinoma (OSCC) cells and a novel lncRNAHITTERS(HERPUD1intronictranscript ofER stress) is identified as the most significantly upregulated lncRNA. It is shown thatHITTERSis a nucleus-located lncRNA including two transcript variants.HITTERSlacks an independent promoter but shares the same promoter withHERPUD1.HITTERSis transcriptionally regulated byActivating Transcription Factor (ATF) 6,ATF4,X-Box Binding Protein 1 (XBP1), and DNA methylation. In human OSCC tissues,HITTERSis significantly correlated with OSCC clinicopathological features and prognosis. Gain- and loss-of-function studies reveal thatHITTERSpromotes OSCC proliferation and invasion via influencing the expression of growth factor receptors and the downstream pathways. Once ER stress is triggered,HITTERSsignificantly attenuates ER stress-induced apoptosis both in vivo and in vitro. Mechanically,HITTERSfunctions as RNA scaffold to promote MRE11-RAD50-NBS1 complex formation in the repair of ER stress-induced DNA damage. To sum up, this study presents a novel lncRNA, namelyHITTERS, which links ER stress and DDR together in OSCC.