The Deubiquitinase USP28 Maintains the Expression of PPARγ and Its Inactivation Protects Mice from Diet-Induced NASH and Hepatocarcinoma
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ABSTRACT:
PROVIDER: PRJNA1114710 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29128004_1.fastq.gz | Fastqsanger.gz | |||
| SRR29128004_2.fastq.gz | Fastqsanger.gz | |||
| SRR29128005_1.fastq.gz | Fastqsanger.gz | |||
| SRR29128005_2.fastq.gz | Fastqsanger.gz | |||
| SRR29128006_1.fastq.gz | Fastqsanger.gz |
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Project description:Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease, is one of the leading causes of liver disease worldwide and may further progress to cirrhosis and cancer. However, the pathogenesis of NASH remains unclear, and there is currently only one FDA-approved drug for its treatment; therefore, new therapeutic approaches are urgently needed. Under high-fat diet or obese conditions, PPARγ is activated in the liver to promote lipid storage as droplets, inducing the progression of NASH. We showed that the expression level of USP28 is elevated in the livers of NAFLD/NASH patients. Through dietary induction, including a methionine-choline deficient (MCD) diet and a Western diet (WD) combined with intraperitoneal injection of carbon tetrachloride (CCl4), we established two severe mouse models of NASH and revealed the role of the deubiquitinase USP28. Mechanistically, the hepatic deubiquitinase USP28 directly binds to PPARγ and prevents its own ubiquitination and degradation, thereby regulating its downstream signaling pathways. In the absence of Usp28 or if the DUB is inhibited, PPARγ is downregulated, and the PPAR signaling pathway is inhibited, allowing the cells to mount a defensive response to excessive fat. Both genetic and pharmacological inactivation of Usp28 significantly attenuated the NASH phenotype induced by the MCD diet or WD-CCl4 regimen, as well as WD-CCl4-induced hepatocellular carcinoma in mice.
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Project description:The oncogenic transcription factor Myc is a pleiotropic regulator of RNA Polymerase II (RNAPII)-dependent transcription, DNA replication and DNA damage response pathways. Myc is stringently regulated by the ubiquitin system - for example, ubiquitination controls recruitment of the elongation factor Paf1c, which is critical for several Myc functions. Curiously, a key Myc-targeting deubiquitinase Usp28 also controls cellular response to DNA damage via the mediator protein 53bp1. Usp28 forms stable dimers, but the biological role of Usp28 dimerization is unknown. We show that dimerization limits Usp28 activity and restricts recruitment of Paf1c by Myc. Expression of monomeric Usp28 leads to ectopic Paf1c recruitment and resolution of transcription-replication conflicts, accelerating DNA synthesis. Strikingly, 53bp1 selectively interacts with and stabilizes dimeric Usp28 - depletion of 53bp1 favors formation of Usp28 monomers deregulating DNA replication. Genotoxic stress disrupts 53bp1-Usp28 complexes, promotes formation of Usp28 monomers and recruitment of Paf1 by Myc. This triggers ectopic DNA synthesis during early response to genotoxins, amplifying DNA damage. We propose that dimerization of Usp28 limits aberrant replication at transcriptionally active chromatin to maintain genome stability.
2023-11-09 | PXD037263 | Pride
Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation. RNAseq experiments of E13.5 murine embryonic fibroblasts (MEFs) derived from animals in which Usp28 was either deleted (-/-), wildtype (+/+) or heterozygous (+/-). In a first set of experiments immortalized MEFs of all three genotypes were analysed in biological triplicates. In a second set of experiments immortalized and Ras transformed MEFs of all three genotypes and MEFs which overexpress USP28 (+/+/+) where sequenced in duplicates.
2015-05-01 | E-GEOD-59354 | biostudies-arrayexpress
Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation.
2015-05-01 | GSE59354 | GEO
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Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress
Project description:To investigate the role of USP28 expression in chronic lymphocytic leukemia, we used the CRISPR/Cas9 system to engineer isogenic HG3 cell lines harboring a monoallelic USP28 loss. We then analyzed the transcriptomic profile of these CRISPR/Cas9-generated cell lines by RNA-seq
2025-05-31 | GSE229756 | GEO
Project description:PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent lysosomal degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage response (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.
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Project description:For validating the role Usp28 in regulating mouse ESC self-renewal, sgRNAs were designed to generate Usp28 KO cell lines. We then performed gene expression profiling analysis using data obtained from RNA-seq control (CTL) and Usp28 KO ESCs.
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Project description:SREBP2 controls the expression of enzymes involved in the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol but also provides substrates for protein prenylation, and that is frequently deregulated in cancer. We show here that SREBP2 is a novel substrate for the deubiquitinating enzyme USP28 and that USP28 regulates SREBP2 stability independent of FBXW7. Inhibition of USP28 reduces MVP activity and renders cancer cells highly sensitive to MVP inhibition by statins. Moreover, statin sensitivity of USP28 depleted cells was rescued by the addition of geranyl-geranyl-pyrophosphate, a substrate for protein prenylation. We also provide evidence that SREBP2 participates in the regulation of gene expression signature associated with squamous cell carcinoma (SCC) and that SREBP2 and enzymes of the MVP are overexpressed in SCC from different tissue origins. Finally, deletion of SREBP2 attenuated tumour growth in a mouse model of lung cancer. Our findings suggest that SREBP2 is a novel substrate for USP28 and that combinatorial targeting of the MVP together with USP28 inhibition could be a therapeutic strategy for the treatment of squamous cell carcinomas.
2023-05-16 | GSE204703 | GEO