Journal
CELL CYCLE
Volume 12, Issue 23, Pages 3689-3701Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.26930
Keywords
HIF-1 alpha; CDK1; hypoxia; angiogenesis; cell cycle
Categories
Funding
- NIH [CA135273, CA123258]
- Penn State Hershey Cancer Institute
- NIH/NCI [F32CA174138]
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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-1 alpha 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-1 alpha, independent of its known regulators. Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1 alpha under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1 alpha, reducing its half-life and steady-state levels. In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1 alpha at a previously unidentified regulatory site, Ser668. HIF-1 alpha is stabilized under normoxic conditions during G(2)/M phase via CDK1-mediated phosphorylation of Ser668. A phospho-mimetic construct of HIF-1 alpha 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-1 alpha (S668E) displays increased tumor angiogenesis, proliferation, and tumor growth in vivo compared with wild-type HIF-1 alpha. Thus, we have identified a novel link between CDK1 and HIF-1 alpha 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.
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