PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions.

Jiayi Chen, Mei Li, Yeqing Liu, Tangming Guan, Xiao Yang, Yalei Wen, Yingjie Zhu, Zeyu Xiao, Xiangchun Shen, Haoxing Zhang, Hui Tang, Tongzheng Liu

Cell death and differentiation 2023 Apr

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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).

Citation

Jiayi Chen, Mei Li, Yeqing Liu, Tangming Guan, Xiao Yang, Yalei Wen, Yingjie Zhu, Zeyu Xiao, Xiangchun Shen, Haoxing Zhang, Hui Tang, Tongzheng Liu. PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions. Cell death and differentiation. 2023 Apr;30(4):1082-1095