PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions

Abstract

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.

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation

“…The phosphorylation of HIF-1α is essential for its transcriptional activity and disrupts interaction with PHD-and pVHL-mediated protein degradation, significantly enhancing the stability of this oncoprotein [148]. Pin1 also interacts with CDK1-phophorylated pVHL, recruiting the E3 ligase WSB1 and facilitating pVHL ubiquitination and degradation [11]. Interrupting the Pin1/CDK1/pVHL axis results in decreased cancer cell proliferation, migration, invasion, and chemoresistance, and therefore it could be therapeutically valuable in treating cancers with wild-type VHL [11].…”

“…Pin1 also interacts with CDK1-phophorylated pVHL, recruiting the E3 ligase WSB1 and facilitating pVHL ubiquitination and degradation [11]. Interrupting the Pin1/CDK1/pVHL axis results in decreased cancer cell proliferation, migration, invasion, and chemoresistance, and therefore it could be therapeutically valuable in treating cancers with wild-type VHL [11].…”

“…Pin1 uniquely binds and catalyzes cis-trans conformational changes at specific phosphorylated Ser/Thr-Pro motifs [7][8][9], thereby modulating the activities, functions, and stabilities of a broad range of substrates after phosphorylation. Notable Pin1 substrates include several master regulators, such as p65/RelA nuclear factor-kappaB (NF-κB) [10], cyclin-dependent kinases (CDKs) [11], and the tumor suppressor protein p53 [12]. Accordingly, as Pin1 is a critical and dynamic signaling regulator for many substrates in essential functions, such as the cell cycle, immunity, and metabolism [13][14][15], it is widely distributed at both the cellular and tissue levels, depending on its substrates [16].…”