Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription.

Abstract

Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in breast cancer cells. In turn, PRMT1 enhances the expression of HIF1α-driven glycolytic genes. Mechanistically, PRMT1 methylates HIF2β at arginine 42, facilitating the formation, chromatin binding, and the transcriptional activity of the HIF1α/HIF2β heterodimer. Genetic and pharmacological inhibition of PRMT1 suppresses HIF2β methylation, HIF1α/HIF2β heterodimer formation, chromatin binding, glycolytic gene expression, lactate production, and the malignant behaviors of breast cancer cells. Moreover, combination treatment with iPRMT1, a PRMT1 inhibitor, and menadione, an HIF1α/P300 interaction inhibitor, demonstrates synergistic effects in suppressing breast tumor growth. Clinically, PRMT1 and PRMT1-mediated HIF2β methylation were significantly elevated in breast tumors compared with adjacent normal tissues. In conclusion, our findings reveal the critical role of PRMT1-mediated arginine methylation in glycolytic gene expression, metabolic reprogramming, and breast tumor growth.