Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus.
Am J Hum Genet
; 108(9): 1590-1610, 2021 09 02.
Article
en En
| MEDLINE
| ID: mdl-34390653
ABSTRACT
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Cromosomas Humanos Par 14
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Carcinoma de Células Renales
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Proteínas de Unión al ADN
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Factor de Transcripción STAT3
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Sitios Genéticos
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Neoplasias Renales
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Am J Hum Genet
Año:
2021
Tipo del documento:
Article
País de afiliación:
Brasil