ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m(6)A-dependent manner

N(6)-methyladenosine (m(6)A) is the most prevalent RNA modification, and the effect of its dysregulation on esophageal squamous cell carcinoma (ESCC) development remains unclear. Here, by performing transcriptome-wide m(6)A sequencing in 16 ESCC tissue samples, we identified the key roles of m(6)A in TNFRSF1A (also known as TNFR1)-mediated MAPK and NF-κB activation in ESCC. Mechanistically, a functional protein involved in m(6)A methylation, ATXN2, is identified that augments the translation of TNFRSF1A by binding to m(6)A-modified TNFRSF1A mRNA. Upregulation of the TNFRSF1A protein level, a vital upstream switch for TNFRSF1A-mediated signaling events, activates the NF-κB and MAPK pathways and thus promotes ESCC development. Furthermore, TNFRSF1A m(6)A modifications and protein levels are upregulated in ESCC, and high levels of TNFRSF1A m(6)A and protein are correlated with poor ESCC patient survival. These results collectively indicate that the m(6)A-TNFRSF1A axis is critical for ESCC development and thus may serve as a potential druggable target.