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USP20 promotes T-ALL evolution by deubiquitinating modified HIF1A

ABSTRACT: USP20 promotes T-ALL evolution by deubiquitinating modified HIF1A

PROVIDER: PRJNA1110766 | ENA |

REPOSITORIES: ENA

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USP20 promotes T-ALL evolution by deubiquitinating modified HIF1A

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy. The potential of investigating USP20 holds promise for more targeted therapies and better outcomes. Knocking down USP20 led to decreased T-ALL cell survival and growth both in vitro and in vivo, similar to using the USP20 inhibitor GSK2643943A. To explore USP20-dependent gene regulation, RNA-seq analysis was conducted and the differently expressed genes were revealed in the USP20-knockdown J.gamma1 cells in comparison to control group. Cleavage Under Targets and Tagmentation (CUT&Tag) showed the co-localization of USP20 with HIF1a on chromatin in J.gamma1 cells.

2025-08-31 | GSE267258 | GEO

Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.

2022-06-07 | GSE186419 | GEO

USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

2021-07-27 | GSE158458 | GEO

Endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3

Project description:Endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3

| PRJNA898372 | ENA

Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time-frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten(i)pe-/- mice which recapitulate prostate carcinogenesis in humans. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, which enhances malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity leading to the emergence of cells with selective Transglutaminase 2 (TGM2) expression and impaired androgen signaling. Importantly, elevated TGM2 levels in PCa patients are associated with shortened progression-free survival after prostatectomy. Finally, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention, and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.

2022-06-07 | GSE189784 | GEO

ZHX2 Promotes HIF1a Oncogenic Signaling in Triple-Negative Breast Cancer

Project description:ZHX2 Promotes HIF1a Oncogenic Signaling in Triple-Negative Breast Cancer

| PRJNA732468 | ENA

Prostate-specific Oncogene OTUD6A Promotes Prostatic Tumorigenesis via Deubiquitinating and Stabilizing c-Myc

Project description:Prostate-specific Oncogene OTUD6A Promotes Prostatic Tumorigenesis via Deubiquitinating and Stabilizing c-Myc

| PRJNA784264 | ENA

Ubiquitin specific peptidase 7 promotes TP53 mutant malignancy by deubiquitinating and stabilizing DDR1

Project description:Ubiquitin specific peptidase 7 promotes TP53 mutant malignancy by deubiquitinating and stabilizing DDR1

| PRJNA1284252 | ENA

SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

Project description:Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect. RNA isolated from brown adipose tissue of SIRT3 WT and KO mice. 5 wild-type samples and 5 SIRT3 KO samples

2011-03-15 | E-GEOD-27309 | biostudies-arrayexpress

Transcriptional studies on the deubiquitinating enzyme Ubp10

Project description:Transcriptional analises of ubp10 null mutant, wild type and related null mutants. Keywords = deubiquitinating enzymes Keywords = yeast Keywords: repeat sample

2004-02-01 | GSE804 | GEO

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