USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness.

ABSTRACT: Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy-related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-β signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-β signaling to promote HIF-2α positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-β downstream effector, stabilizes HIF-2ɑ in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-β signals converge on USP9X-HIF-2ɑ axis via multi-level reg

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC12006517 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature