The deubiquitinase USP9X and E3 ligase WWP1 orchestrate IGF2BP2 ubiquitination homeostasis to drive TNBC progression and cisplatin sensitivity.

ABSTRACT: The functional impact of post-translational modifications (PTMs) on many N6-methyladenosine (m6A) regulatory proteins remains unclear. Our previous study demonstrated that the m6A reader IGF2BP2 drives triple-negative breast cancer (TNBC) progression through epigenetic regulation. Here, we found that IGF2BP2 ubiquitination homeostasis was dynamically regulated by the opposing actions of USP9X (deubiquitinase) and WWP1 (E3 ligase). We further identified USP9X as a cisplatin-binding protein, whose inactivation upon cisplatin treatment shifts this balance toward WWP1-mediated IGF2BP2 degradation in TNBC. This suppressed IGF2BP2-mediated stabilization and translation of m6A-modified MYC/CDK6 mRNAs, thereby inhibiting TNBC progression. Notably, combined USP9X inhibitor WP1130 and low-dose cispl

SUBMITTER: Xia T 

PROVIDER: S-EPMC12500958 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature