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

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

PROVIDER: PRJNA1209069 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31956587_1.fastq.gz	Fastqsanger.gz
	SRR31956587_2.fastq.gz	Fastqsanger.gz
	SRR31956588_1.fastq.gz	Fastqsanger.gz
	SRR31956588_2.fastq.gz	Fastqsanger.gz
	SRR31956589_1.fastq.gz	Fastqsanger.gz

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

Project description: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 regulations, which in turn facilitates Smad/HIF responses. Clinically, USP9X expression correlates with TGF-β signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-β signaling, and a downstream USP9X-HIF-2ɑ proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-β signaling in CSCs and meliorate clinical chemoresistance.

2025-04-05 | GSE286397 | GEO

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

Project 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.

2024-03-08 | PXD050476 |

Loss of Usp9x increases Wnt and Notch signaling in neural progenitors

Project description:Correct neural progenitor fate determination requires the coordination of extrinsic fate determinant signals with intrinsic responses. Post-translational modifications dynamically alter protein function and so are ideally situated to regulate development. Here we show that the deubiquitylaying enzyme, Usp9x modulates both intrinsic and extrinsic regulators of mouse neural progenitors. Nestin-cre mediated deletion of Usp9x from neural progenitors results in a transient disruption of cell adhesion and apical-basal polarity as well as the premature differentiation of intermediate neural progenitors. Ablation of Usp9x also significantly increased Î²-catenin protein levels, especially S33/S37/T41 phospho-Î²-catenin, and Wnt signalling. Usp9x was found to be part of the Î²-catenin destruction complex and loss of Usp9x affects destruction complex composition. Notch signalling was also increased in Usp9x ablated neural progenitors, coinciding with decreased Itch and Numb, and increased Notch intracellular domain protein levels. Usp9x co-localized and immunopreciptiated with Numb from neural progenitors suggesting it is required for Numb stabilisation. These data suggest Usp9x plays a role in coordinating intrinsic responses to extrinsic signals during neural development.

2017-08-18 | E-MTAB-4150 | biostudies-arrayexpress

The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development

Project description:Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of the global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.

2021-01-25 | GSE146800 | GEO

Deubiquitinase USP9X regulates Wnt-signaling to control CNS vascular formation and barrier maintenance

Project description:Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific Usp9x knockout reduces Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we uncovered β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological models of impaired CNS vascular barrier function, including an intracerebral hemorrhage model and an oxygen-induced retinopathy model, loss of Usp9x intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.

2024-12-13 | GSE281249 | GEO

Deubiquitinase USP9X regulates Wnt-signaling to control CNS vascular formation and barrier maintenance [Human]

2024-12-13 | GSE281250 | GEO

High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [RNA-seq]

Project description:High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [RNA-seq]

| PRJNA1189593 | ENA

High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [ChIP-seq]

Project description:High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [ChIP-seq]

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High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [CRISPR screen]

Project description:High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in ovarian cancer [CRISPR screen]

| PRJNA1189595 | ENA