HADHA promotes esophageal cancer progression by activating mTOR signaling and the SP1/MDM2 axis

Esophageal cancer (EC) is one of the most recalcitrant cancers, with a 5-year survival rate of < 30%. The hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) plays an essential role in long-chain fatty acid metabolism, and dysregulation of HADHA has been demonstrated to be involved in a series of metabolic diseases and cancers. However, its role in cancers remains controversial. HADHA has seldom been investigated in EC, and little is known about how HADHA regulates the malignant progression of EC. In this study, we find that HADHA is significantly upregulated in EC tissues and is correlated with poor survival. <i>HADHA</i> knockdown markedly inhibits EC cell proliferation both <i>in vitro</i> and <i>in vivo</i>. The loss of HADHA also induces EC cell apoptosis, causes cell cycle arrest and inhibits cell migration. Additionally, RNA profiling reveals that mTOR signaling is significantly suppressed after <i>HADHA</i> knockdown. Mechanistically, HADHA interacts with SP1 and induces MDM2 expression. In conclusion, both mTOR signaling and the SP1-MDM2 axis participate in the HADHA-induced malignant behavior of EC cells.