LAUSR

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent malignancies with a 5‐year survival rate of only 15% in patients with advanced diseases. Tumor protein 63 (TP63), a master transcription factor (TF) in ESCC, cooperates with other TFs to regulate enhancers and/or promoters of target oncogenes, which in turn promotes tumorigenesis. TAR‐DNA‐binding protein‐43 (TDP‐43) is an RNA/DNA binding protein with elevated expression in several neoplasms. However, it remains unclear how TDP‐43 contributes to ESCC progression. In this study, TDP‐43 is identified as a novel oncogene with markedly upregulated expression in ESCC tissues through profiling expression levels of one hundred and fifty canonical RNA binding protein (RBP) genes in multiple ESCC patient cohorts. Importantly, TDP‐43 boosted TP63 expression via post‐transcriptionally stabilizing TP63 mRNAs as a RBP and promoting TP63 transcription as a TF binding to the TP63 promoter in ESCC cells. In contrast, the master TF TP63 also bound to the TDP‐43 promoter, accelerated TDP‐43 transcription, and caused a noticeable increase in TDP‐43 expression in ESCC cells. The findings highlight TDP‐43 as a viable therapeutic target for ESCC and uncover a hitherto unrecognized TDP‐43/TP63 circuit in cancer.