A-kinase anchoring protein 17 A promotes hypoxic adaptation and tumor growth by augmenting HIF1α protein synthesis

Hypoxia-inducible factor 1α (HIF1α) is the master transcriptional regulator of cellular adaptation to low oxygen microenvironment, essential for oxygen homeostasis and promoting tumorigenesis. We report that AKAP17A, an A-kinase anchoring protein, activates HIF1α signaling through a protein kinase A (PKA)-independent mechanism. Depletion of AKAP17A in mammalian cells reduced HIF1α abundance and attenuated the transcriptional activation of HIF target genes. Consistently, akap17a-null zebrafish exhibited compromised HIF signaling, impaired hypoxia tolerance, and diminished hypoxia-induced erythropoiesis. Functionally, knocking out AKAP17A suppressed cancer cell proliferation in vitro and impeded tumor growth in vivo. Mechanistic investigations revealed that AKAP17A augments HIF1α protein synthesis. Collectively, this work identifies AKAP17A as a pivotal regulator of the HIF1α, providing novel insights into its role in hypoxic adaptation and oncogenesis.