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

Abstract

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 1α (HIF-1α) 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-1α-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-1α-dependent glycolysis in HL60 and HL60/ADR cells. Furthermore, 2-deoxy-glucose (2-DG) exposure inhibited HIF-1α-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.

Crosstalk between the lncRNA UCA1 and microRNAs in cancer

“…Additionally, UCA1 conferred imatinib resistance in chronic ML as a ceRNA of multidrug resistance protein-1 (MDR1), which induced imatinib resistance by sequestering miR-16 [142]. In addition, UCA1 also conferred the resistance of adriamycin, a chemotherapy drug used for the treatment of AML, by sponging the miR-125a targeting HK2 to promote glycolysis [145]. In addition, UCA1 also conferred the resistance of adriamycin, a chemotherapy drug used for the treatment of AML, by sponging the miR-125a targeting HK2 to promote glycolysis [145].…”

The implication of lncRNA expression pattern and potential function of lncRNA RP4‐576H24.2 in acute myeloid leukemia

“…And lncRNA ANRIL enhances the malignant cell survival and cell glucose metabolism of AML by regulating the AdipoR1/AMPK/SIRT1 pathway . In addition, lncRNA UCA1 expression is increased in AML pediatric patients after adriamycin (ADR)‐based chemotherapy, and knockdown of lncRNA UCA1 inhibits chemoresistance to ADR in AML cells via mediating miR‐125a/hexokinase 2 pathway . And lncRNA TUG1 suppresses AML cell proliferation while promotes apoptosis through targeting aurora kinase A .…”

“…In AML, the studies aiming at investigating the role of lncRNA are limited, while the findings are minimal yet intriguing. Previous studies reveal that some specific lncRNAs might play crucial roles in regulating the AML cell functions or chemoresistance, for instance, a previous study reports that lncRNA urothelial carcinoma‐associated 1 (UCA1) knockdown inhibits chemoresistance via repressing glycolysis by mediating the microRNA (miR)‐125a/hexokinase 2 signaling pathway . However, the existed studies mostly focus on investigating the roles of several specific/individual lncRNAs in AML, such as lncRNA antisense noncoding RNA in the INK4 locus (ANRIL), lncRNA UCA1 and so on, while the studies assessing the lncRNA expression pattern in AML are few …”

“…Previous studies reveal that some specific lncRNAs might play crucial roles in regulating the AML cell functions or chemoresistance, for instance, a previous study reports that lncRNA urothelial carcinoma-associated 1 (UCA1) knockdown inhibits chemoresistance via repressing glycolysis by mediating the microRNA (miR)-125a/hexokinase 2 signaling pathway. 11,12 However, the existed studies mostly focus on investigating the roles of several specific/individual lncRNAs in AML, such as lncRNA antisense noncoding RNA in the INK4 locus (ANRIL), lncRNA UCA1 and so on, while the studies assessing the lncRNA expression pattern in AML are few. 11,13 Herein, we conducted this study to investigate the implication of lncRNA expression pattern in AML pathogenesis and the potential of several specific candidate lncRNAs as markers for AML risk and prognosis, and further explore the effect of lncRNA RP4-576H24.2 on regulating AML progression.…”

“…13 In addition, lncRNA UCA1 expression is increased in AML pediatric patients after adriamycin (ADR)-based chemotherapy, and knockdown of lncRNA UCA1 inhibits chemoresistance to ADR in AML cells via mediating miR-125a/hexokinase 2 pathway. 11 And lncRNA TUG1 suppresses AML cell proliferation while promotes apoptosis through targeting aurora kinase A. 12 Furthermore, a recent experiment reveals that lncRNA SNHG1 promotes cell proliferation through mediating miR-488-5p/NUP205 axis in AML.…”