Knockdown of LncRNA-UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA-125a/hexokinase 2 pathway

Dysregulation of lncRNAs is implicated in chemoresistance in varieties of tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma-associated 1 (UCA1) was reported to play an oncogenic role in AML. However, whether UCA1 was involved in chemoresistance in pediatric AML remains unclear. UCA1 expression in AML patients after adriamycin (ADR)-based chemotherapy and ADR-resistant AML cells was examined by qRT-PCR. The effects of UCA1 on the cytotoxicity of ADR and glycolysis were evaluated by MTT assay and measuring the glucose consumption and lactate production in HL60 and HL60/ADR cells, repectively. The protein levels of hypoxia-inducible factor 1 (HIF-1) and hexokinase 2 (HK2) were determined by Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the relationships between UCA1, HK2, and miR-125a. We found that UCA1 expression was upregulated following ADR-based chemotherapy. Knockdown of UCA1 increased the cytotoxic effect of ADR and inhibited HIF-1-dependent glycolysis in ADR-resistant AML cells. Additionally, UCA1 functioned as a ceRNA of miR-125a by directly binding to miR-125a. HK2, a target of miR-125a, was positively regulated by UCA1 in HL60 and HL60/ADR cells. More notably, UCA1 overexpression overturned miR-125-mediated inhibition on HIF-1-dependent glycolysis in HL60 and HL60/ADR cells. Furthermore, 2-deoxy-glucose (2-DG) exposure inhibited HIF-1-dependent glycolysis, and attenuated UCA1-induced increase of chemoresistance in HL60 and HL60/ADR cells. We conclude that knockdown of UCA1 plays a positive role in overcoming the chemoresistance of pediatric AML, through suppressing glycolysis by the miR-125a/HK2 pathway, contributing to a better understanding of the molecular mechanism of chemoresistance in AML.