The transcription factor HAND1 suppresses endometrial cancer progression by regulating fatty acid β-oxidation via c-MET
Endometrial cancer (EC) is the second most common malignancy in the female reproductive system, yet its pathogenesis remains unclear. The transcription factor HAND1, a potential tumor suppressor, has an undefined role in EC progression. In this study, we found that HAND1 expression was significantly downregulated in EC tissues and negatively correlated with the malignant behaviors of EC cells. Transcriptomic and metabolomic analyses revealed that HAND1 overexpression markedly downregulated c-MET expression and facilitated the accumulation of acylcarnitine. Mechanistic studies demonstrated that c-MET could rescue the effects of HAND1 on EC cell proliferation, migration, invasion, and tumorigenicity. Further investigation revealed that upregulation of HAND1 significantly suppressed CPT2 expression via inhibition of c-MET, resulting in attenuated fatty acid β-oxidation (FAO) activity, reduced expression of electron transport chain complexes, diminished ATP synthesis, and a decline in mitochondrial membrane potential. Collectively, this study elucidates the molecular mechanism by which the HAND1/c-MET axis regulates EC progression through the modulation of FAO. This provides a novel perspective for understanding the pathogenesis of EC and offers potential biomarkers for developing novel diagnostic and therapeutic strategies for EC.