Neoadjuvant chemotherapy (NAC) is a key component of the standard treatment regimen for patients with advanced esophageal squamous cell carcinoma (ESCC); however, a substantial proportion of patients fail to benefit from NAC because of intrinsic or acquired chemoresistance, leading to disease progression. Aberrant promoter methylation of tumor suppressor genes has been implicated in the diminished chemotherapy response in patients with ESCC. In this study, we show that hypermethylation of the CpG island of the T-box Transcription Factor 1 (TBX1) promoter is frequently associated with nonresponse to NAC in patients with ESCC. Functional experiments indicate that TBX1 suppresses ESCC cell proliferation, induces apoptosis, and increases cisplatin sensitivity. Mechanistically, TBX1 activates the Hippo signaling pathway through two complementary mechanisms: transcriptional upregulation of MST1 and LATS1 and inhibition of F-actin polymerization. Restoration of TBX1 expression enhances chemosensitivity and reduces tumor growth in vivo. Collectively, our findings suggest that TBX1 promoter hypermethylation has the potential to serve as a predictive biomarker of the NAC response in ESCC and define an epigenetic mechanism in which TBX1 silencing contributes to chemoresistance through impairment of Hippo pathway activation. These results suggest that modulating TBX1 expression and Hippo pathway activity represents a potential therapeutic strategy for overcoming chemoresistance in ESCC.
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