USP9X coordinates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via maintaining cancer stem cells

ABSTRACT: Widespread intraperitoneal metastases and chemoresistance has made 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. Whereas, how the signaling is activated and how to target TGF-β signaling precisely remain as key challenges. Here, we identify hypoxic tumor microenvironment as the initiator of TGF-β signaling so as to induce HIF-2α positive CSCs and chemoresistance in HGSOC. Mechanistically, deubiquitinase USP9X, as the TGF-β downstream effector, stabilizes HIF-2ɑ in hydroxylation and ubiquitylation dependent manner, thus activates stemness programming. Hypoxia and TGF-β signals promote USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses, thus coordinating the two pathways. Clinical USP9X is highly correlated with TGF-β signatures, CSCs characteristics, EMT behaviors, and stimulated by chemotherapies, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increases chemosensitivity, through orthotopic tumor, patient derived xenograft (PDX), organoid and chemoresistant cell models, via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in turning up TGF-β signaling, as well as USP9X-HIF-2ɑ proteostatic regulation in priming the HGSOC stemness, thus provides a promising strategy to counteract TGF-β signaling by targeting USP9X in CSCs and meliorate clinical chemoresistance.

ORGANISM(S): Homo Sapiens

SUBMITTER: Li Zhao  

PROVIDER: PXD050476 | iProX | Fri Mar 08 00:00:00 GMT 2024

REPOSITORIES: iProX