Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus
| Autor: | David R. Mole, Lea Jessop, Virginia Schmid, Mitchell J. Machiela, Olivier Delattre, Grace C. Mills, Jiyeon Choi, Mark P. Purdue, Renato Cunha, Stephen J. Chanock, Leandro M. Colli, Olusegun O. Onabajo, Seth A. Brodie, Sabrina Y. Camp, Kai Yu, Kevin M. Brown, Timothy A. Myers |
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| Rok vydání: | 2021 |
| Předmět: |
STAT3 Transcription Factor
Carcinogenesis Locus (genetics) medicine.disease_cause Polymorphism Single Nucleotide Cell Line Tumor Gene expression Genetics medicine Humans Genetic Predisposition to Disease STAT3 Carcinoma Renal Cell Genetics (clinical) Chromosomes Human Pair 14 Reporter gene biology Genome Human High-Throughput Nucleotide Sequencing Chromatin Assembly and Disassembly Chromatin Kidney Neoplasms SWI/SNF DNA-Binding Proteins Gene Expression Regulation Genetic Loci biology.protein Cancer research Cytokines Cytokine secretion Immunotherapy Genome-Wide Association Study T-Lymphocytes Cytotoxic Transcription Factors |
| Zdroj: | The American Journal of Human Genetics. 108:1590-1610 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2021.07.009 |
| Popis: | Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation. |
| Databáze: | OpenAIRE |
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