VHL蛋白(pVHL)通过调节蛋白底物如HIF1α和Akt的降解或激活来发挥肿瘤抑制剂的功能。在携带野生型VHL的人类癌症中，pVHL的异常下调通常被检测到并且对肿瘤进展起关键作用，然而，这些癌症中pVHL稳定性被调节的潜在机制仍然不清楚。在此，我们在多种携带野生型VHL的人类癌症中，包括三阴性乳腺癌(TNBC)，确定了环素依赖性激酶1(CDK1)和肽前脯氨酸顺反异构酶NIMA相互作用1(PIN1)作为两个先前未表征的pVHL调控因子。PIN1和CDK1共同调节pVHL的蛋白质转化，从而在体内外赋予肿瘤生长、化疗抗性和转移的能力。在机械方面，CDK1直接磷酸化pVHL的Ser80，从而为PIN1对pVHL的认知做好了铺垫。然后，PIN1结合磷酸化的pVHL，促进E3连接酶WSB1的招募，从而将pVHL定向去泛素化和降解。此外，通过RO-3306和全反式视黄酸(ATRA)基因消融或药物抑制CDK1和PIN1（急性早幼粒细胞白血病的标准治疗）能够显著抑制肿瘤生长、转移并提高癌细胞对化疗药物的敏感性，这取决于pVHL的依赖性。组织学分析表明，在TNBC样本中，PIN1和CDK1的表达水平较高，与pVHL的表达呈负相关。综上所述，我们的研究揭示了CDK1 / PIN1轴通过不稳定pVHL的未被认知的肿瘤促进功能，并提供了靶向CDK1 / PIN1的治疗携带野生型VHL的多种癌症的临床前证据。©2023.作者。

The VHL protein (pVHL) functions as a tumor suppressor by regulating the degradation or activation of protein substrates such as HIF1α and Akt. In human cancers harboring wild-type VHL, the aberrant downregulation of pVHL is frequently detected and critically contributes to tumor progression. However, the underlying mechanism by which the stability of pVHL is deregulated in these cancers remains elusive. Here, we identify cyclin-dependent kinase 1 (CDK1) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) as two previously uncharacterized regulators of pVHL in multiple types of human cancers harboring wild-type VHL including triple-negative breast cancer (TNBC). PIN1 and CDK1 cooperatively modulate the protein turnover of pVHL, thereby conferring tumor growth, chemotherapeutic resistance and metastasis both in vitro and in vivo. Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation. Furthermore, the genetic ablation or pharmacological inhibition of CDK1 by RO-3306 and PIN1 by all-trans retinoic acid (ATRA), the standard care for Acute Promyelocytic Leukemia could markedly suppress tumor growth, metastasis and sensitize cancer cells to chemotherapeutic drugs in a pVHL dependent manner. The histological analyses show that PIN1 and CDK1 are highly expressed in TNBC samples, which negatively correlate with the expression of pVHL. Taken together, our findings reveal the previous unrecognized tumor-promoting function of CDK1/PIN1 axis through destabilizing pVHL and provide the preclinical evidence that targeting CDK1/PIN1 is an appealing strategy in the treatment of multiple cancers with wild-type VHL.© 2023. The Author(s).