HADHA overexpression disrupts lipid metabolism and inhibits tumor growth in clear cell renal cell carcinoma.

Hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) is a key lipid metabolic enzyme with a novel role in carcinogenesis. We previously reported that HADHA, a prognostic marker, was downregulated in clear cell renal cell carcinoma (ccRCC). Herein, the tumor inhibitory role of HADHA overexpression in ccRCC was investigated further. The quantitative proteomic analysis displayed that a total of 1293 and 1293 proteins were identified in HADHA overexpressed 786-O-hadha and vector-transfected control 786-O-vc cells, respectively, and 206 proteins were found to be up- or downregulated. PANTHER, OmicsNet, STRING, and DAVID tools were utilized on the dysregulated proteins in order to elucidate multiple metabolic pathways (especial lipid metabolism) and lipid metabolism-related proteins (e.g. ACAT1, ACLY). The dysregulation of the lipid metabolic enzymes, ACAT1, ACLY, CYB5R3 and FASN, were confirmed by Western blotting. Further assays demonstrated that HADHA overexpression significantly inhibited cell growth, induced cell apoptosis, and decreased the formation of cytoplasmic lipid droplets (LDs); moreover, it also inhibited tumor growth and lessened the formation of LDs in xenografted mouse. Collectively, these data revealed that HADHA overexpression disrupted lipid metabolism and inhibited tumor growth, which shed light on HADHA as a potential therapeutic target for clinical intervention of ccRCC.