AbstractBackground InformationCancer cells acquire malignant characteristics and therapy resistance by employing the hypoxia‐inducible factor 1 (HIF‐1)‐dependent adaptive response to hypoxic microenvironment in solid tumors. Since the underlying molecular mechanisms remain unclear, difficulties are associated with establishing effective therapeutic strategies.ResultsWe herein identified DEAD‐box helicase 5 (DDX5) as a novel activator of HIF‐1 and found that it enhanced the heterodimer formation of HIF‐1α and HIF‐1β and facilitated the recruitment of the resulting HIF‐1 to its recognition sequence, hypoxia‐response element (HRE), leading to the expression of a subset of cancer‐related genes under hypoxia.ConclusionsThis study reveals that the regulation of HIF‐1 recruitment to HRE is an important regulatory step in the control of HIF‐1 activity.SignificanceThe present study provides novel insights for the development of strategies to inhibit the HIF‐1‐dependent expression of cancer‐related genes.