Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions

Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial-mesenchymal transition (EMT), contributes to self-renewal of cancer stem-like cells (CSCs), chemo-resistance, metastasis, and TNBC-related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1-mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven-malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor-promoting function and clinical significance of the CDK1-USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo-resistance and metastasis in TNBC.

Automated summary

The study reveals the role of TWIST1 in triple-negative breast cancer (TNBC) and identifies USP29 as a deubiquitinase that stabilizes TWIST1. It is found that CDK1 functions as the activator of USP29 and its phosphorylation is important for TWIST1 deubiquitination. CDK1 and USP29 are highly upregulated in TNBC samples, which correlates with TWIST1 expression. Targeting the CDK1-USP29 axis could be a promising therapeutic strategy for overcoming chemo-resistance and metastasis in TNBC.