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USP1 identified as an important factor in the progression of gastric cancer

ABSTRACT: Gastric cancer is one of the leading causes of cancer-related deaths, and through in vivo and in vitro genetic screens, we identified USP1 as an important factor in promoting tumor progression. Here, we analyzed the transcriptome of sh-USP after knockdown with the aim of identifying downstream effectors of USP1

ORGANISM(S): Homo sapiens

PROVIDER: GSE282776 | GEO | 2024/12/01

REPOSITORIES: GEO

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USP1 identified as an important factor in the progression of gastric cancer

Project description:USP1 identified as an important factor in the progression of gastric cancer

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Ubiquitinated PCNA drives USP1 synthetic lethality in cancer

Project description:CRISPR Cas9-based functional genomics screening is a powerful approach for identifying and characterizing novel oncology drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacological inhibition of USP1 leads to decreased DNA synthesis concomitant with the induction of S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identified RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as downstream mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition was associated with a reduction in total PCNA protein levels. Ectopic expression of WT and ubiquitin-dead K164R PCNA reversed USP1 inhibitor sensitivity. Our results demonstrate, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to a novel subset of BRCA1/2 WT cancer enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant cell lines and xenograft models. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to post-translational modifications of PCNA. Taken together, USP1 inhibition may represent a unique therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.

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NAT10 is identified as a novel driver for brain metastasis

Project description:Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Using in vivo and in vitro genetic screens, we identified NAT10 as a driver for breast cancer brain metastassis. Here, we profile the transcriptome of metastatic breast cancer cells MDA-MB-231-BrM3 following NAT10 knockdown, aiming to identify the downstream effectors of NAT10.

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Gene expression changes in breast cancer cells upon USP1 knockdown [RNA-Seq]

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USP1 modulates hepatocellular carcinoma progression via Hippo/TAZ axis

Project description:To investigate the function of USP1 in the HCC.

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USP1 expression driven by EWS-FLI1 transcription factor stabilizes Survivin and promotes Ewing sarcoma cell survival

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The deubiquitinase cofactor UAF1 interacts with USP1 and plays an essential role in spermiogenesis

Project description:Spermiogenesis defines the final phase of male germ cell differentiation. Multiple deubiquitinating enzymes have been linked to spermiogenesis, yet the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis and male fertility. We selectively deleted Uaf1 in premeiotic germ cells using Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. We found that UAF1 interacts and colocalizes with USP1 in testes. Conditional knockout of Uaf1 in testes results in disturbed expression and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. We used tandem mass tag-based proteomics to identify differentially expressed proteins and potential underlying mechanisms, and found that conditional knockout Uaf1 in testes results in reduced levels of proteins essential for spermiogenesis. Thus, the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

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PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-mediated Survival of Proneural Glioma Cells.

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