CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth

Noel A. Warfel, Nathan G. Dolloff, David T. Dicker, Jozef Malysz, Wafik S. El-Deiry

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a major mediator of tumor physiology, and its activation is correlated with tumor progression, metastasis, and therapeutic resistance. HIF-1 is activated in a broad range of solid tumors due to intratumoral hypoxia or genetic alterations that enhance its expression or inhibit its degradation. As a result, decreasing HIF-1α expression represents an attractive strategy to sensitize hypoxic tumors to anticancer therapies. Here, we show that cyclin-dependent kinase 1 (CDK1) regulates the expression of HIF-1α, independent of its known regulators. Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1α under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1α, reducing its half-life and steady-state levels. In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1α at a previously unidentified regulatory site, Ser668. HIF-1α is stabilized under normoxic conditions during G2/M phase via CDK1-mediated phosphorylation of Ser668. A phospho-mimetic construct of HIF-1α at Ser668 (S668E) is significantly more stable under both normoxic and hypoxic conditions, resulting in enhanced transcription of HIF-1 target genes and increased tumor cell invasion and migration. Importantly, HIF-1α (S668E) displays increased tumor angiogenesis, proliferation, and tumor growth in vivo compared with wild-type HIF-1α. Thus, we have identified a novel link between CDK1 and HIF-1α that provides a potential molecular explanation for the elevated HIF-1 activity observed in primary and metastatic tumors, independent of hypoxia, and offers a molecular rationale for the clinical translation of CDK inhibitors for use in tumors with constitutively active HIF-1.

Original languageEnglish (US)
Pages (from-to)3689-3701
Number of pages13
JournalCell Cycle
Volume12
Issue number23
DOIs
StatePublished - Dec 1 2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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    Warfel, N. A., Dolloff, N. G., Dicker, D. T., Malysz, J., & El-Deiry, W. S. (2013). CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth. Cell Cycle, 12(23), 3689-3701. https://doi.org/10.4161/cc.26930