Abstract

ABSTRACT Hypoxia is a hallmark of solid tumors, and hypoxia‐inducible factors (HIFs) are the master transcription factors that allow cancer cells to sense and cope with a hypoxic microenvironment. However, the mechanism by which the HIF‐mediated transcription process is precisely regulated remains poorly understood. Here, we demonstrate that the RNA helicase DDX21 facilitates breast tumor growth and metastasis by triggering HIF‐mediated transcription elongation. Mechanistically, DDX21 induces the release of CDK9 from the 7SK complex, enhancing the interaction between CDK9 and HIF‐1α. This interaction stimulates the transcription elongation of HIF target genes by elevating the enrichment of phosphorylated RNA Polymerase II at serine 2 on the hypoxia‐response element of HIF target genes. These target genes, including IGFBP1, WNT1, WNT10B, TGFB1, PCK1, and SLC2A3, are critical for cancer cell proliferation and metastasis. Consequently, DDX21 enhances breast cancer cell proliferation, survival, migration, and invasion in vitro, and promotes breast tumor growth and metastasis in vivo. Importantly, DDX21 is highly expressed in breast tumors and correlates negatively with clinical outcomes in breast cancer patients. Our study reveals a novel mechanism of HIF regulation and positions DDX21 as a potential therapeutic target for disrupting the hypoxic adaptation machinery in breast cancer.