ARID1A mutations in cancer: another epigenetic tumor suppressor?

Abstract

Although disordered chromatin organization has long been recognized as a feature of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: frequent mutation of epigenetic regulators. Among these, the ARID1A/BAF250A subunit of the SWI/SNF (BRG1-associated factors) chromatin remodeling complex has emerged as recurrently mutated in a broad array of tumor types. We review the genomic and functional data supporting classification of ARID1A as a tumor suppressor.

Significance: Mutations in chromatin remodeling complex genes are increasingly recognized in many cancer types. However, the mechanisms by which chromatin remodeling complexes contribute to gene expression and the cancer phenotype are poorly understood. Understanding how mutation of chromatin remodelers facilitates transformation may offer the potential for development and implementation of novel therapies for cancer.

Figure 1

ARID1A Domain Structure and Protein Interactions A) Map of ARID1A, highlighting protein homology domains, putative protein-protein interaction domains, post-translational modifications and the difference in the two isoforms. B) Six main classes of protein have been reported to co-immunoprecipitate with ARID1A: 1) the SWI/SNF complex; 2) transcription factors; 3) coactivator/corepressor complexes; 4) histone modifying enzymes; 5) ubiquitin ligase machinery, and 6) tumor suppressors.

Figure 1

ARID1A Domain Structure and Protein Interactions A) Map of ARID1A, highlighting protein homology domains, putative protein-protein interaction domains, post-translational modifications and the difference in the two isoforms. B) Six main classes of protein have been reported to co-immunoprecipitate with ARID1A: 1) the SWI/SNF complex; 2) transcription factors; 3) coactivator/corepressor complexes; 4) histone modifying enzymes; 5) ubiquitin ligase machinery, and 6) tumor suppressors.

Figure 2

Contributions of the SWI/SNF Complex to Chromatin Structure and Transcriptional Regulation Several functions have been ascribed to the SWI/SNF complex, including 1) mobilizing nucleosomes at promoters, enhancers, and/or gene bodies; 2) facilitating the binding of transcription factors; 3) recruiting coactivator/corepressor complexes; 4) recruiting histone modifying enzymes; and 5) facilitating chromatin looping to facilitate enhancer and promoter interaction.