AC137932.2 reinforces hypoxia-driven glycolytic remodeling in triple-negative breast cancer through an IGF2BP2/HIF-1α...

Triple-negative breast cancer (TNBC) displays aggressive progression and pronounced hypoxia-driven metabolic remodeling. However, whether the long non-coding RNA AC137932.2 mechanistically links hypoxia signaling to glycolysis in TNBC through maintenance of HIF-1α output remains unclear.

TCGA-BRCA data were used to analyze AC137932.2 expression, its prognostic value, and its correlation with glycolysis-related genes and VEGFA. AC137932.2 levels were measured in breast cancer cell lines and hypoxia-treated TNBC cells via qRT‒PCR. Loss-of-function and rescue assays were performed in MDA-MB-231 and BT-549 cells. Cell viability, EdU incorporation, invasion, ATP content, glucose consumption, lactate production, extracellular acidification rate (ECAR), glycolysis, and glycolytic capacity were examined. RIP-qPCR, actinomycin D chase, dual-luciferase reporter, and ChIP‒qPCR assays were used to clarify the AC137932.2/IGF2BP2/HIF-1α mechanism.

AC137932.2 was upregulated in breast cancer tissues and TNBC cells, was associated with poor prognosis, and was positively correlated with glycolysis-related genes and VEGFA. Hypoxia induced AC137932.2 expression in MDA-MB-231 and BT-549 cells. AC137932.2 knockdown suppressed TNBC cell viability, proliferation, invasion, ATP production, glucose consumption, lactate production, the ECAR, glycolysis, and glycolytic capacity under both normoxia and hypoxia. Mechanistically, AC137932.2 was mainly localized in the cytoplasm and interacted with IGF2BP2. AC137932.2 stabilized HIF-1α mRNA through IGF2BP2, while HIF-1α bound to the AC137932.2 promoter and activated its transcription. IGF2BP2 or HIF-1α overexpression partially rescued the inhibitory effects of AC137932.2 knockdown on TNBC malignancy and glycolysis.

AC137932.2 promotes TNBC proliferation, invasion, and glycolytic reprogramming by forming an AC137932.2/IGF2BP2/HIF-1α positive feedback loop, suggesting that this axis may be a potential therapeutic target for TNBC.