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OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition

ABSTRACT: OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition

PROVIDER: PRJNA973945 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24639210_1.fastq.gz	Fastqsanger.gz
	SRR24639210_2.fastq.gz	Fastqsanger.gz
	SRR24639211_1.fastq.gz	Fastqsanger.gz
	SRR24639211_2.fastq.gz	Fastqsanger.gz
	SRR24639212_1.fastq.gz	Fastqsanger.gz

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OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition

Project description:These findings delineate the mechanism of OTUB2 epigenetic silencing in ovarian cancer, demonstrate the critical roles of OTUB2/SNX29P2 in inhibiting glycolysis and eliciting cuproptosis in cancer cells and suggest that CA9 inhibitor treatment is a promising therapeutic option for OTUB2-silenced tumors. To investigate the downstream pathway regulated by OTUB2/SNX29P2, we performed RNA sequencing (RNA-seq) in ES-2 cells expressing EV, OTUB2 or SNX29P2.

2024-04-19 | GSE232772 | GEO

Soybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinoma

Project description:Soybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinoma

| PRJNA721679 | ENA

Soybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinoma

Project description:Oral and esophageal squamous cell carcinomas (SCCs) are associated with high mortality, yet molecular mechanisms underlying these malignancies are largely unknown. We demonstrate that epigenetic silencing of otubain 2 (OTUB2), a previously recognized oncogene, drives SSCs initiation and drug resistance. Mechanistically, OTUB2 promotes deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1), then activates transcriptional regulation of calmodulin-like protein 3 (CALML3). Activation of CALML3-mediated mitochondrial calcium signaling promotes oxidative phosphorylation (OXPHOS) and glycerophospholipid synthesis, among which phosphatidylserine (PS) is the most obviously affected. Orally administered soybean-derived PS dramatically inhibits low-OTUB2-expressed SCC initiation and increased sensitivity to chemotherapy in various mouse models. Our study indicates that the OTUB2/STAT1/CALML3/PS axis plays a critical tumor-suppressive role in SCCs, clarifies the low incidence of oral and esophageal SCCs in Western countries with a high-fat diet and demonstrates the potential of food supplementation with PS as a strategy for treatment and prevention of SCCs.

2022-09-19 | GSE172001 | GEO

OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition.

Project description: Not available

| S-EPMC11087800 | biostudies-literature

Analysis of the differential expression of genes in Otub2- knockout mice

2022-09-19 | GSE171878 | GEO

The Deubiquitinating Enzyme Otub2 Modulates Pancreatic Beta-Cells Function and Survival

Project description:We have previously shown that otubain 2 (OTUB2), a deubiquitinating enzyme, inhibits caspase-3/7 activity in primary human islets; promotes insulin secretion and inhibits cytokine-induced nuclear factor-κB (NFκB) activity. In the present work we show that overexpression of Otub2 in MIN6 cells inhibits NFκB activity and the expression of its target genes MCP-1 and iNOS. Consequently, both the basal and the cytokine-induced apoptosis of cultured MIN6 cells and dispersed human islets were inhibited. Overexpression of Otub2 in MIN6 cells increase the mRNA levels of NKx6.1 and Glut2 and concomitantly increased glucose-stimulated insulin secretion (GSIS) (by 2-3-fold). The beneficial effects of Otub2 on β-cell function was demonstrated by the phenotype of Otub2-/+ and Otub2-/- mice, which manifested impaired glucose tolerance and increased expression of NFkB target genes (e.g. IP-10, MCP-1 and IL-1b). RNAseq analysis of pancreata derived from OTUB2 KO mice revealed reduced expression of genes that down regulate K+ transporters (e.g. Ank2, Cacna1a and Kcnab1) combined with an increase in oxidative phosphorylation related genes. Given that closure of K+ channels is crucial for insulin secretion, these results could account, at least in part, for the impaired GSIS in the OTUB2 KO mice. Indeed, mass-spectrometry analysis of proteins co-immunoprecipitated with Otub2 revealed the voltage-gated potassium channel subunit Kv9.3 as a major Otub2 binding-partner. Additional binding partners included the Peg3 and Camk2d proteins, which promote NFκB signaling and β-cell death. Hence, by deubiquitinating proteins in complexes that contain Peg3 and Camk2d, Otub2 might inhibit propagation of NFκB signaling and β-cell apoptosis. Collectively our findings implicate Otub2 as a key regulator of b cell function, mainly affecting NFkB signaling and the K+ channels that regulate insulin secretion.

2026-03-25 | GSE285973 | GEO

Cellular Validation of Chemically Improved Inhibitor Identifies Monoubiquitination on OTUB2

Project description:Ubiquitin thioesterase OTUB2, a cysteine protease from the ovarian tumor (OTU) deubiquitinase superfamily, is associated with enhanced expression during tumor progression and metastasis. Development of OTUB2 inhibitors is therefore believed to be therapeutically important, yet potent and selective small-molecule inhibitors targeting OTUB2 are scarce. Here, we describe the development of an improved OTUB2 inhibitor, LN5P45, comprising a chloroacethydrazide moiety that covalently reacts to the active-site cysteine residue. When added to cells, LN5P45 shows outstanding target engagement and proteome-wide selectivity. Importantly, we found that LN5P45 and the other OTUB2 inhibitors strongly induce monoubiquitination of OTUB2 via lysine 31. Thus, our findings provide novel insights for the design of future OTUB2-related therapeutics and open new questions regarding the understanding of OTUB2 regulation at the post-translational modification level.

2023-06-27 | PXD041346 | Pride

OTUB2/NR4A1 restrains the development of preeclampsia by suppressing macrophage M1 polarization

Project description:Preeclampsia is one of the most common pregnancy disorders, and characterized by insufficient trophoblast invasion and placental inflammation. RNA sequencing was performed using placental tissues collected from PE patients and control healthy pregnant women. The results showed that OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) was downregulated in placenta from PE patients.

2025-08-20 | GSE303543 | GEO

Ubiquitin Thioesterase OTUB2 is An Endoplasmic Reticulum Stress-associated β Cell Autoantigen Targeted by CD8+ T cells in Type 1 Diabetes

Project description:Autoreactive CD8+ T cell plays a key role in the pathogenesis of Type 1 diabetes (T1D), but the antigen spectrum that activate autoreactive CD8+ T cells is still not completely clear. Endoplasmic reticulum stress（ERS）has been implicated in the generation of β cell autoantigens and the enhanced immune visibility of β cells to autoreactive T cells. Here, we in-depth analyzed the major histocompatibility complex class I (MHC-I) associated immunopeptidome (MIP) of islets β cell under steady-state and ERS-state, and found couples of peptides exclusively present in the MIP of β cell line under ERS state. Among them, peptide OTUB258-66 derived from ubiquitin thioesterase OTUB2 showed immunodominance in NOD mice, and autoreactive CD8+ T cells targeting OTUB258-66 were diabetogenic in NOD mice. High glucose intake upregulated the expression of OTUB2 in the pancreas and amplified the OTUB258-66-specific CD8+ T cell response in NOD mice. Repeated administration with OTUB258-66 significantly reduced the incidence of T1D in NOD mice. This study not only provides an explanation for the role of ERS induced by environmental factors such as high glucose intake in promoting β cell autoimmune injury, but also provides a novel ERS-associated β cell autoantigens for developing specific immune intervention in prevention and treatment of T1D.

2024-05-24 | PXD041227 | Pride

A synthetically methylotrophic Escherichia coli as a chassis for bioproduction

Project description:Proteome characterization of three E. coli strains: a methanol-dependent strain (MEvo1-0) and two synthetically methylotrophic strains (MEcoli_ref_1, MEcoli_ref_2)

2024-02-08 | PXD046243 | Pride

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