Related Experiment Video
Updated: May 21, 2026
In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
Published on: July 25, 2019
BAP1 loss defines a new class of renal cell carcinoma
Samuel Peña-Llopis1, Silvia Vega-Rubín-de-Celis, Arnold Liao
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
Insights
The BAP1 gene is inactivated in 15% of clear cell renal cell carcinomas (RCCs), impacting cell proliferation and stress response. Combined BAP1 and PBRM1 loss correlates with aggressive RCC features.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The molecular mechanisms driving renal cell carcinoma (RCC) remain largely unknown.
- Identifying key genetic alterations is crucial for understanding RCC pathogenesis and developing targeted therapies.
Purpose of the Study:
- To identify novel tumor suppressor genes involved in RCC development.
- To investigate the functional consequences of BAP1 inactivation in RCC.
- To explore the relationship between BAP1, PBRM1, and RCC progression.
Main Methods:
- Whole-genome and exome sequencing of RCC tumors.
- Tumorgraft analyses to determine mutant allele ratios.
- Functional assays assessing BAP1's role in cell proliferation, deubiquitination, and stress response.
- Analysis of gene expression and mutation correlations.
Main Results:
- BAP1, a nuclear deubiquitinase, was identified as a putative tumor suppressor gene inactivated in 15% of clear cell RCCs.
- BAP1 mutations affecting its HCF-1 binding motif impaired cell proliferation suppression but not histone deubiquitination.
- BAP1 loss sensitized RCC cells to genotoxic stress.
- Mutations in BAP1 and PBRM1 showed significant anticorrelation in tumors.
- Combined loss of BAP1 and PBRM1 was associated with rhabdoid features and high tumor grade in a subset of RCCs.
Conclusions:
- BAP1 is a critical tumor suppressor in RCC, influencing cell proliferation and stress response.
- The interplay between BAP1 and PBRM1 may drive specific RCC subtypes with aggressive features.
- These findings support an integrated molecular-genetic classification of RCC for developing targeted treatments.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...