P53-P21-RB pathway promotes BRD4 degradation in liver cancer through decreasing USP1 transcription
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1020749 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26160516_1.fastq.gz | Fastqsanger.gz | |||
| SRR26160516_2.fastq.gz | Fastqsanger.gz | |||
| SRR26160517_1.fastq.gz | Fastqsanger.gz | |||
| SRR26160517_2.fastq.gz | Fastqsanger.gz | |||
| SRR26160518_1.fastq.gz | Fastqsanger.gz |
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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: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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Project description:Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the pro-tumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer.
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Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
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Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
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Project description:In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb.
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