Abstract
Polybromo-1 (PBRM1) is a component of the PBAF (Polybromo-associated-BRG1- or BRM-associated factors) chromatin remodeling complex and is the second most frequently mutated gene in clear-cell renal cell Carcinoma (ccRCC). Mutation of PBRM1 is believed to be an early event in carcinogenesis, however its function as a tumor suppressor is not understood. In this study, we have employed Next Generation Sequencing to profile the differentially expressed genes upon PBRM1 re-expression in a cellular model of ccRCC. PBRM1 re-expression led to upregulation of genes involved in cellular adhesion, carbohydrate metabolism, apoptotic process and response to hypoxia, and a downregulation of genes involved in different stages of cell division. The decrease in cellular proliferation upon PBRM1 re-expression was confirmed, validating the functional role of PBRM1 as a tumor suppressor in a cell-based model. In addition, we identified a role for PBRM1 in regulating metabolic pathways known to be important for driving ccRCC, including the regulation of hypoxia response genes, PI3K signaling, glucose uptake, and cholesterol homeostasis. Of particular novelty is the identification of cell adhesion as a major downstream process uniquely regulated by PBRM1 expression. Cytoskeletal reorganization was induced upon PBRM1 reexpression as evidenced from the increase in the number of cells displaying cortical actin, a hallmark of epithelial cells. Genes involved in cell adhesion featured prominently in our transcriptional dataset and overlapped with genes uniquely regulated by PBRM1 in clinical specimens of ccRCC. Genes involved in cell adhesion serve as tumor suppressor and maybe involved in inhibiting cell migration. Here we report for the first time genes linked to cell adhesion serve as downstream targets of PBRM1, and hope to lay the foundation of future studies focusing on the role of chromatin remodelers in bringing about these alterations during malignancies.
Highlights
Kidney cancer is among the ten most common cancers in America, comprising approximately 62,000 new cancer cases and 14,000 deaths every year
Renal cell carcinoma (RCC) is the most common (~80%) and lethal type of kidney cancer in adults with clear cell RCC as the most prevalent and aggressive subtype [1, 2]. ccRCC is named for its characteristic histological appearance caused by high glycogen and lipid content resulting from a glycolytic metabolic shift to a “Warburg effect”-like state [3]
Conclusion ccRCC is a metabolic cancer characterized by a shift to aerobic glycolysis facilitated by alterations in hypoxia transcriptional pathways
Summary
Kidney cancer is among the ten most common cancers in America, comprising approximately 62,000 new cancer cases and 14,000 deaths every year. In order to better understand genetic events causing ccRCC, exome sequencing of patient tumors has uncovered several novel genes significantly mutated in ccRCC, all of which encode for proteins that regulate chromatin. These novel genes include Polybromo-1 (PBRM1), BAP1, SETD2, KDM5C, and KDM6A. BAF complexes use energy from ATP to regulate transcription by altering chromatin structure and the placement of Polycomb across the genome. Subunits of the BAF complex are mutated in over 20% of human tumors [10, 11] yet the mechanisms involved in tumor suppression are still unclear
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