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786-O LC-MS/MS - Loss of BAP1 Results in Growth Inhibition and Enhances Mesenchymal-Epithelial Transition in Kidney Tumor Cells

ABSTRACT: BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C‑terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with clear cell renal cell carcinoma (ccRCC), the most common form of renal cancer, suggesting that BAP1 may be a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing WT BAP1 is unclear. Here, we assessed the expression and function of BAP1 using human ccRCC specimens and cell lines.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Kidney

DISEASE(S): Renal Clear Cell Carcinoma

SUBMITTER: Pengsheng Chen

LAB HEAD: Haiteng Deng

PROVIDER: PXD012288 | Pride | 2019-04-18

REPOSITORIES: Pride

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Loss of BAP1 Results in Growth Inhibition and Enhances Mesenchymal-Epithelial Transition in Kidney Tumor Cells.

Chen Pengsheng P Wang Huan H Zhang Wenhao W Chen Yuling Y Lv Yang Y Wu Di D Guo Mingzhou M Deng Haiteng H

Molecular & cellular proteomics : MCP 20190416 7

BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with ccRCC, the most common form of renal cancer, suggesting that BAP1 is a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing wild-type (WT) BAP1 is unclear. Here, we assessed the expression and function of BAP1 using ...[more]

PMID: 30992312

Similar Datasets

786-O ubiquitiome - Loss of BAP1 Results in Growth Inhibition and Enhances Mesenchymal-Epithelial Transition in Kidney Tumor Cells

Project description:786-O WT and BAP1-KO cells were cultured in heavy (13C6-L-arginine, 13C6-L-lysine, Cambridge Isotope Lab) and light (unlabeled L-arginine and L-lysine) SILAC RPMI-1640 medium (Thermo Fisher Scienific), respectively. After more than 10 passages, cells were lysed with 8 M urea and 5 mg protein from each group were mix. The ubiquitinated peptide enrichment was performed using PTMScan® (Cell Signaling Technology, #5562) following the manufacturer’s instructions.

2019-04-18 | PXD013127 | Pride

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice retained >92% of mutations and exhibited similar DNA copy number alterations to corresponding primary tumors. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The genomic DNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal samples were labeled and hybridized to Affymetrix SNP arrays 6.0.

2012-06-09 | E-GEOD-25540 | biostudies-arrayexpress

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The RNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal kidney cortices were labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays.

2012-06-09 | E-GEOD-36895 | biostudies-arrayexpress

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

2012-06-10 | GSE25540 | GEO

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

2012-06-10 | GSE36895 | GEO

Bap1 loss results in EZH2 dependent transformation

Project description:Analysis of sorted granulocyte macrophage progenitors (GMPs) in control and Bap1-deficient bone marrow cells. Loss of Bap1 in the hematopoietic compartments results in an MDS-like disease. These data allow for the examination of the genetic underpinnings of Bap1 loss in disease.

2015-10-05 | GSE61577 | GEO

Bap1 loss results in EZH2 dependent transformation

Project description:BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated Ezh2 expression, and enhanced repression of Polycomb Repressive Complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone.

2015-10-05 | GSE61360 | GEO

Expression data form mouse partial hepatectomy in Kras mutant and Bap1 deleted / Kras mutant mice

Project description:BAP1 is a nuclear deubiquitinating enzyme in the ubiquitin carboxyterminal-hydrolase subfamily that is involved in chromatin remodeling. It has been demonstrated to function as a tumor suppressor gene in multiple human malignancies. Molecular studies have found recurrent somatic mutations in BAP1 in intrahepatic cholangiocarcinoma. We have characterized the role of BAP1 in ICC development through a combination of whole genome ChIP-on-chip and transcriptional profiling of the mouse hepatic tumors. In this dataset, we include the expression data obtained from dissected mouse livers containing tumors using a gain-of-function mutation in KRAS (G12D), as well as loss-of-function mutation in BAP1. These data are used to obtain genes that are differentially expressed in response to Bap1 loss.

2021-11-29 | GSE183554 | GEO

A pan-cancer study to identify and characterize synthetic lethal drugs in BAP1-deficient cancers

Project description:BRCA-1 Associated Protein (BAP1) is a deubiquitinating enzyme that acts as a tumour suppressor. Inactivating mutations in the BAP1 gene have been identified in many cancers including cholangiocarcinoma, hepatocellular carcinoma, mesothelioma, uveal melanoma and renal cell carcinoma. Current standard therapeutic approaches for BAP1-deficient tumours are not particularly promising, contributing to poor overall survival and disease-free survival rates. Here, we found BAP1 to mediate the turnover of the key proteins in the DNA nucleotide excision repair (NER) pathway, and therefore promotes DNA repair. Importantly, we demonstrate that the loss of functional BAP1 sensitise tumour cells to LSD1 inhibitor, SP2509, in vitro and in vivo, through further impairment of NER efficiency. When used in combination with PARP1 inhibitor, Olaparib, we show that a synergistic drug combination response is achieved. Overall, our study identifies a drug combination approach that has the potential to be exploited clinically to target BAP1 deficient tumours.

2022-09-15 | PXD028470 | JPOST Repository

Genetic screens reveal new targetable vulnerabilities in BAP1-deficient Mesothelioma

Project description:More than half of malignant mesothelioma patients show alterations in the BAP1 tumour suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome which may create new vulnerabilities that remain largely unknown. Here we performed a CRISPR/Cas9-kinome screen in mesothelioma cells that identified two kinases in the Mevalonate/Cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression and genetic perturbation data in mesothelioma cells suggests a dependency on Polycomb repressive complex 2 (PRC2) mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (Zoledronic Acid) and PRC2 inhibition (Tazemetostat), we demonstrate a potent anti-tumour effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma

2023-01-12 | GSE222376 | GEO

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