PXD050476

PXD050476 is an original dataset announced via ProteomeXchange.

Title	USP9X coordinates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via maintaining cancer stem cells
Description	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.
HostingRepository	iProX
AnnounceDate	2024-03-08
AnnouncementXML	Submission_2025-08-28_23:57:23.603.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zhenlei Zhang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-08 01:47:30	ID requested
⏵ 1	2025-08-28 23:57:25	announced

Zhang Z, Yu X, Wen L, Wang J, Li Z, Zhang Y, Cheng J, Kan R, Zhang W, Shen Y, Yuan S, Zhao L, -maintained stemness. Cell Death Dis, 16(1):312(2025) [pubmed]

submitter keyword: AP-MS, USP9X, HIF-2α

Li Zhao
contact affiliation	Tianjin Medical University
contact email	shzhaoli@tmu.edu.cn
lab head
Zhenlei Zhang
contact affiliation	Tianjin Medical University
contact email	zhangzhenlei0413@tmu.edu.cn
dataset submitter

iProX dataset URI