ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner

Abstract

N⁶-methyladenosine (m⁶A) 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 m⁶A sequencing in 16 ESCC tissue samples, we identified the key roles of m⁶A in TNFRSF1A (also known as TNFR1)-mediated MAPK and NF-κB activation in ESCC. Mechanistically, a functional protein involved in m⁶A methylation, ATXN2, is identified that augments the translation of TNFRSF1A by binding to m⁶A-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 m⁶A modifications and protein levels are upregulated in ESCC, and high levels of TNFRSF1A m⁶A and protein are correlated with poor ESCC patient survival. These results collectively indicate that the m⁶A-TNFRSF1A axis is critical for ESCC development and thus may serve as a potential druggable target.