Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus

Am J Hum Genet. 2021 Sep 2;108(9):1590-1610. doi: 10.1016/j.ajhg.2021.07.009. Epub 2021 Aug 13.

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.

Keywords: ATAC-seq; GWAS; MPRA; SWI/SNF; apoptosis; enhancer; hypoxia; immunotherapy; massively parallel reporter assay; renal cancer; susceptibility loci biology.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Carcinogenesis / pathology
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / therapy
  • Cell Line, Tumor
  • Chromatin / chemistry
  • Chromatin / immunology
  • Chromatin Assembly and Disassembly / immunology
  • Chromosomes, Human, Pair 14*
  • Cytokines / genetics
  • Cytokines / immunology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Gene Expression Regulation
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome, Human
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunotherapy / methods
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / pathology
  • Kidney Neoplasms / therapy
  • Polymorphism, Single Nucleotide
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / immunology
  • T-Lymphocytes, Cytotoxic
  • Transcription Factors / genetics*
  • Transcription Factors / immunology

Substances

  • Chromatin
  • Cytokines
  • DNA-Binding Proteins
  • DPF3 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factors