USP1 identified as an important factor in the progression of gastric cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1190402 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31508700_1.fastq.gz | Fastqsanger.gz | |||
| SRR31508700_2.fastq.gz | Fastqsanger.gz | |||
| SRR31508701_1.fastq.gz | Fastqsanger.gz | |||
| SRR31508701_2.fastq.gz | Fastqsanger.gz | |||
| SRR31508702_1.fastq.gz | Fastqsanger.gz |
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Project description: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
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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.
2022-09-27 | GSE214121 | GEO
Project description:NeuroD1-USP1-N-Myc axis drives tumor progression in neuroblastoma
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Project description:To explore the function of deubiquitinase USP1 in breast cancer cells, we performed RNA sequencing to analyze the expression pattern changes by knockdown of USP1 in MCF7 cells.
2021-03-14 | GSE111838 | GEO
Project description:Liver cancer claims over 800,000 human deaths each year. Liver cancer is notoriously refractory to conventional therapeutics. Further insight into the etiology carries promise for innovative diagnostics and therapeutics. Tumor progression is governed by interplay between tumor promoting genes and suppressor genes. BRD4, an acetyl-lysine binding protein, plays a critical role in development and human diseases. In many cancer types, BRD4 is overexpressed and promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains elusive. As BRD4 has risen as a promising therapeutic target, to understand the mechanism regulating BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we find BRD4 protein level in liver cancer is significantly regulated by P53, the most frequently dysregulated tumor suppressor. We identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. We then show P53 promotes BRD4 protein degradation. Mechanistically, P53 represses the transcription of USP1, a deubiquitinase, through P21-RB. We show USP1 is a deubiquitinase of BRD4, which increases its stability. We show the pro-tumor role of USP1 is partially mediated by BRD4 and the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB-USP1-BRD4 axis in liver cancer.
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Project description:Two miRNA arms from the same precursor, miR-574-5p and miR-574-3p, were reversely expressed and played exact opposite role in gastric cancer progression. miR-574-5p/-3p ratio was also strongly correlated with higher TNM stages and shorter survival of patients. The increase of miR-574-5p/-3p ratio, or the arm-imbalance of miR-574 was due to the dynamic expression of their highly complementary targets in gastric carcinogenesis. The arm imbalance of miR-574 in turn strongly contributed to and further promoted gastric cancer progression. Conclusion: Our findings indicated that targets mediated miR-574 arm-imbalance contributed to gastric cancer progression. Re-modification of the miR-574-targets homeostasis may represent a realistic approach for gastric cancer prevention and therapy. Two miRNA arms from the same precursor, miR-574-5p and miR-574-3p, were reversely expressed and played exact opposite role in gastric cancer progression. miR-574-5p/-3p ratio was also strongly correlated with higher TNM stages and shorter survival of patients. The increase of miR-574-5p/-3p ratio, or the arm-imbalance of miR-574 was due to the dynamic expression of their highly complementary targets in gastric carcinogenesis. The arm imbalance of miR-574 in turn strongly contributed to and further promoted gastric cancer progression. Conclusion: Our findings indicated that targets mediated miR-574 arm-imbalance contributed to gastric cancer progression. Re-modification of the miR-574-targets homeostasis may represent a realistic approach for gastric cancer prevention and therapy. Two miRNA arms from the same precursor, miR-574-5p and miR-574-3p, were reversely expressed and played exact opposite role in gastric cancer progression. miR-574-5p/-3p ratio was also strongly correlated with higher TNM stages and shorter survival of patients. The increase of miR-574-5p/-3p ratio, or the arm-imbalance of miR-574 was due to the dynamic expression of their highly complementary targets in gastric carcinogenesis. The arm imbalance of miR-574 in turn strongly contributed to and further promoted gastric cancer progression. Our findings indicated that targets mediated miR-574 arm-imbalance contributed to gastric cancer progression. Re-modification of the miR-574-targets homeostasis may represent a realistic approach for gastric cancer prevention and therapy.
2019-08-25 | GSE133629 | GEO
Project description:Two miRNA arms from the same precursor, miR-574-5p and miR-574-3p, were reversely expressed and played exact opposite role in gastric cancer progression. miR-574-5p/-3p ratio was also strongly correlated with higher TNM stages and shorter survival of patients. The increase of miR-574-5p/-3p ratio, or the arm-imbalance of miR-574 was due to the dynamic expression of their highly complementary targets in gastric carcinogenesis. The arm imbalance of miR-574 in turn strongly contributed to and further promoted gastric cancer progression. Conclusion: Our findings indicated that targets mediated miR-574 arm-imbalance contributed to gastric cancer progression. Re-modification of the miR-574-targets homeostasis may represent a realistic approach for gastric cancer prevention and therapy.
2019-08-28 | GSE112859 | GEO
Project description:Background: The lack of obvious symptoms of early gastric cancer (GC) as well as the absence of sensitive and specific biomarkers results in poor clinical outcomes. Tubulin is currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders, however, its mechanism of action in gastric cancer is still unclear. Tubulin alpha-1C(TUBA1C) is a subtype of α-tubulin, high TUBA1C expression has been shown to be closely related to a poor prognosis in in various cancers,this study, for the first time, revealed the mechanism of TUBA1C promotes malignant progression of gastric cancer in vitro and in vivo. Methods: The expression of lncRNA EGFR-AS1 was detected in human GC cell lines by qRT–PCR. Mass spectrometry experiments following RNA pulldown assays found that EGFR-AS1 directly binds to TUBA1C, the CCK8, EdU, transwell, wound-healing, cell cycle assays and animal experiments were conducted to investigate the function of TUBA1C in GC. Combined with bioinformatics analyses, reveal interaction between Ki-67, E2F1, PCNA and TUBA1C by western blot. Rescue experiments furtherly demonstrated the relationship of EGFR-AS1and TUBA1C. Results: TUBA1C was proved to be a direct target of EGFR-AS1, TUBA1C promotes gastric cancer proliferation, migration and invasion by accelerating the progression of the cell cycle from the G1 phase to the S phase and activating the expression of oncogenes: Ki-67,E2F1 and PCNA. Conclusions: TUBA1C is a new potential target of LncRNA EGFR-AS1 promotes gastric cancer progression and could be a novel biomarker and therapeutic target for GC.
2023-05-10 | PXD040199 | Pride