Long Noncoding RNA MIR210HG Promotes the Warburg Effect and Tumor Growth by Enhancing HIF-1α Translation in Triple-Negative Breast Cancer

Abstract

BACKGROUND: Hypoxia is an important environmental factor and has been correlated with tumor progression, treatment resistance and poor prognosis in many solid tumors, including triple-negative breast cancer (TNBC). Emerging evidence suggests that long noncoding RNA (lncRNA) functions as a critical regulator in tumor biology. However, little is known about the link between hypoxia and lncRNAs in TNBC. METHODS: TNBC molecular profiles from The Cancer Genome Atlas (TCGA) were leveraged to identify hypoxia-related molecular alterations. Loss-of-function studies were performed to determine the regulatory role of MIR210HG in tumor glycolysis. The potential functions and mechanisms of hypoxia-MIR210HG axis were explored using qPCR, Western blotting, luciferase reporter assay, and polysome profiling. RESULTS: We found that MIR210HG is a hypoxia-induced lncRNA in TNBC. Loss-of-function studies revealed that MIR210HG promoted the Warburg effect as demonstrated by glucose uptake, lactate production and expression of glycolytic components. Mechanistically, MIR210HG potentiated the metabolic transcription factor hypoxia-inducible factor 1α (HIF-1α) translation via directly binding to the 5'-UTR of HIF-1α mRNA, leading to increased HIF-1a protein level, thereby upregulating expression of glycolytic enzymes. MIR210HG knockdown in TNBC cells reduced their glycolytic metabolism and abolished their tumorigenic potential, indicating the glycolysis-dependent oncogenic activity of MIR210HG in TNBC. Moreover, MIR210HG was highly expressed in breast cancer and predicted poor clinical outcome. CONCLUSION: Our results decipher a positive feedback loop between hypoxia and MIR210HG that drive the Warburg effect and suggest that MIR210HG may be a good prognostic marker and therapeutic target for TNBC patients.