HECW2 knockdown suppresses the development of infantile hemangioma by inhibiting ALKBH5/LDHA axis-mediated glycolysis

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 (HECW2), a member of E3 ubiquitin ligase family, was identified as a hub gene in infantile hemangioma (IH). This study investigated the roles and mechanisms of HECW2 in IH development. Our investigation revealed that HECW2 was up-regulated in proliferative and involuting IH tissues compared with normal adjacent tissues. Hemangioma endothelial cells (HemECs) were isolated and transfected with over-expressed HECW2 or knockdown plasmids. Functional studies demonstrated that HECW2 over-expression facilitated proliferation, migration, invasion as well as inhibited apoptosis in HemECs. Furthermore, over-expressed HECW2 markedly promoted glycolysis in HemECs, as evidenced by increased glucose uptake, lactate production, and adenosine triphosphate (ATP) generation. In contrast, HECW2 knockdown showed the opposite results. Mechanistically, HECW2 regulated the ubiquitination of AlkB homolog 5 (ALKBH5), subsequently enhancing the expression of lactate dehydrogenase A (LDHA) through ALKBH5-mediated m6A demethylation of LDHA mRNA. HECW2 knockdown suppressed glycolysis and tumor-like cellular behaviors in HemECs, which were abrogated by LDHA over-expression. Additionally, in vivo validation using an IH xenograft mouse model demonstrated that HECW2 knockdown significantly suppressed tumor growth. These findings established HECW2 as a key regulator in IH progression through the regulation of ALKBH5/LDHA-mediated glycolysis, suggesting its potential as a therapeutic target for IH treatment.