Abstract
The abnormal expression of PHAX was observed in esophageal cancer, however, its specific function and mechanism remain to be further elucidated. We demonstrated that PHAX, LIN28B, and PBX3 were upregulated in esophageal cancer, while TET2 was downregulated. Elevated PHAX correlated with adverse outcomes among esophageal cancer patients. PHAX or PBX3 knockdown not only inhibited esophageal cancer cell proliferation, and promoted apoptosis and autophagy in vitro, but it also repressed tumor growth and lung metastasis in mice. Mechanically, PHAX stabilized PBX3 mRNA through interacting with LIN28B. PBX3 directly bound to the TET2 promoter region and inhibited its expression. In conclusion, PHAX directly bound to LIN28B and enhanced LIN28B-mediated stabilization of PBX3 mRNA, leading to upregulation of PBX3. PBX3 then transcriptionally repressed TET2 expression to promote esophageal cancer cell proliferation, and suppress apoptosis and autophagy. Targeting this signaling cascade could represent a promising therapeutic strategy for esophageal cancer.