Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors

Andrea L. Casillas, Shailender S. Chauhan, Rachel K. Toth, Alva G. Sainz, Amber N. Clements, Corbin C. Jensen, Paul R. Langlais, Cindy K. Miranti, Anne E. Cress, Noel A. Warfel

Research output: Contribution to journalArticlepeer-review

Abstract

Angiogenesis is essential for the sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Therefore, understanding the mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis. Herein, we establish a new regulatory mechanism responsible for the constitutive activation of HIF-1α in cancer, irrespective of oxygen tension. PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits. In vitro and in vivo models demonstrate that expression of PIM1 is sufficient to stabilize HIF-1α and HIF-2α in normoxia and stimulate angiogenesis in a HIF-1-dependent manner. CRISPR mutants of HIF-1α (Thr455D) promoted increased tumor growth, proliferation, and angiogenesis. Moreover, HIF-1α-T455D xenograft tumors were refractory to the anti-angiogenic and cytotoxic effects of PIM inhibitors. These data identify a new signaling axis responsible for hypoxia-independent activation of HIF-1 and expand our understanding of the tumorigenic role of PIM1 in solid tumors.

Original languageEnglish (US)
Pages (from-to)5142-5152
Number of pages11
JournalOncogene
Volume40
Issue number32
DOIs
StatePublished - Aug 12 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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