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首页> 外文期刊>Cell cycle >CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth
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CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth

机译：CDK1通过Ser668的直接磷酸化来稳定HIF-1α以促进肿瘤生长

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摘要

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.
机译：缺氧诱导因子1（HIF-1）是肿瘤生理学的主要介质，其激活与肿瘤的进展，转移和治疗耐药性相关。由于肿瘤内缺氧或增强其表达或抑制其降解的遗传改变，HIF-1在广泛的实体瘤中被激活。结果，降低HIF-1α表达代表了使缺氧肿瘤对抗癌疗法敏感的有吸引力的策略。在这里，我们表明细胞周期蛋白依赖性激酶1（CDK1）调节HIF-1α的表达，独立于其已知的调节剂。在常氧条件下，CDK1和/或细胞周期蛋白B1的过表达足以稳定HIF-1α，而抑制CDK1则可增强HIF-1α的蛋白酶体降解，从而降低其半衰期和稳态水平。体外激酶测定显示CDK1在先前未确定的调控位点Ser668上直接磷酸化HIF-1α。通过CDK1介导的Ser668磷酸化，HIF-1α在常氧条件下稳定在G2 / M期。 HIF-1α在Ser668（S668E）处的磷酸模拟构建体在常氧和低氧条件下均明显更稳定，从而导致HIF-1靶基因的转录增强，肿瘤细胞的侵袭和迁移增加。重要的是，与野生型HIF-1α相比，HIF-1α（S668E）在体内显示出增加的肿瘤血管生成，增殖和肿瘤生长。因此，我们已经确定了CDK1和HIF-1α之间的新型联系，这为在原发性和转移性肿瘤中观察到的HIF-1活性升高提供了潜在的分子解释，而与缺氧无关，并且为CDK抑制剂的临床翻译提供了分子基础用于具有活性HIF-1的肿瘤。

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