Nonsense-mediated decay factor SMG7 sensitizes cells to TNFα-induced apoptosis via CYLD tumor suppressor and the noncoding oncogenePvt1

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 ofSmg7leads to unrestricted expression of long noncoding RNAs (lncRNAs) in addition to NMD targets. Functional analysis ofSmg7(-/-)cells showed downregulation of the tumor suppressor cylindromatosis (CYLD) and diminished caspase activity, thereby switching cells to nuclear factor-kappa B (NF-kappa B)-mediated protection. This positive relationship betweenSMG7andCYLDwas 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 lncRNAsPvt1andAdapt33rendered cells resistant to TNF, while pharmacologic inhibition of NF-kappa B inPvt1-overexpressing TNF-resistant cells andSmg7-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-kappa B 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.