Nonsense‐mediated decay factor SMG7 sensitizes cells to TNFα‐induced apoptosis via CYLD tumor suppressor and the noncoding oncogene Pvt1

Nonsense‐mediated decay (NMD) proteins are responsible for the surveillance and degradation of aberrant RNAs. Suppressor with morphogenetic effect on genitalia 7 (SMG7) is an NMD complex protein and a regulator of tumor necrosis factor (TNF)‐induced extrinsic apoptosis; however, this unique function has not been explored in detail. In this study, we show that loss of Smg7 leads to unrestricted expression of long noncoding RNAs (lncRNAs) in addition to NMD targets. Functional analysis of Smg7(−/−) cells showed downregulation of the tumor suppressor cylindromatosis (CYLD) and diminished caspase activity, thereby switching cells to nuclear factor‐κB (NF‐κB)‐mediated protection. This positive relationship between SMG7 and CYLD was found to be widely conserved in human cancer cell lines and renal carcinoma samples from The Cancer Genome Atlas. In addition to CYLD suppression, upregulation of lncRNAs Pvt1 and Adapt33 rendered cells resistant to TNF, while pharmacologic inhibition of NF‐κB in Pvt1‐overexpressing TNF‐resistant cells and Smg7‐deficient spheroids re‐established TNF‐induced lethality. Thus, loss of SMG7 decouples regulation of two separate oncogenic factors with cumulative downstream effects on the NF‐κB pathway. The data highlight a novel and specific regulation of oncogenic factors by SMG7 and pinpoint a composite tumor suppressor role in response to TNF.