ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via mA-dependent manner.

N-methyladenosine (mA) 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 mA sequencing in 16 ESCC tissue samples, we identified the key roles of mA in TNFRSF1A (also known as TNFR1)-mediated MAPK and NF-κB activation in ESCC. Mechanistically, a functional protein involved in mA methylation, ATXN2, is identified that augments the translation of TNFRSF1A by binding to mA-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 mA modifications and protein levels are upregulated in ESCC, and high levels of TNFRSF1A mA and protein are correlated with poor ESCC patient survival. These results collectively indicate that the mA-TNFRSF1A axis is critical for ESCC development and thus may serve as a potential druggable target.