Loss of the Epigenetic Tumor Suppressor SNF5 Leads to Cancer without Genomic Instability

Abstract

There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in ␥-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.Many safeguards are in place to prevent a cell from undergoing oncogenic transformation. For example, an average of 14 separate cancer-promoting mutations are required for formation of breast or colon cancer (70). The mechanisms that underlie cancer formation are complex, however, since the low rate of mutation in normal human cells should essentially preclude the independent acquisition of so many mutations. Genome instability may explain this apparent paradox, since early mutations that compromise DNA repair can accelerate the acquisition of subsequent mutations (3). Consistent with this, both DNA repair defects and chromosomal instability are extremely common among highly malignant cancers. However, the cause-and-effect relationships between oncogenesis and genomic instability are not clear, and genetic mutation is not the only mechanism by which stable alteration of gene expression can occur.It has become increasingly clear that epigenetic alterations, those changes in gene expression brought about by altered chromatin context rather than DNA sequence mutations, can also contribute to oncogenic transformation. For example, hypermethylation of DNA in CpG-rich promoter regions can silence tumor suppressor genes. Similarly, expression levels of histone methyltransferases, histone acetyltransferases, and histone deacetylases are frequently altered in cancer cells, as are global levels of histone acetylation and methylation (20,30,67). Recently nucleosome positioning was also implicated in oncogenesis, with the demonstration that heritable cha...

Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors

“…MRT are classified by the complete or partial loss of the SMARCB1 gene on both alleles via inactivating mutations, deletion or allelic loss of chromosome 22q (3). Aside from genomic alterations that lead to inactivation of SMARCB1, MRT is characterized by a remarkably stable genome having the lowest base rate change among all sequenced cancer types (5)(6)(7). This suggests that SMARCB1 inactivation alone is sufficient to initiate MRT, raising the possibility of epigenetic deregulation as causative in the development and pathogenesis of this disease.…”

Srg3, a mouse homolog of BAF155, is a novel p53 target and acts as a tumor suppressor by modulating p21WAF1/CIP1 expression

“…However, another report showed that loss of SNF5 does not affect the sensitivity to DNA damaging agents, g-H2AX induction and their recruitment to sites of DNA damage, and that neither BRG1 nor SNF5 colocalizes with g-H2AX foci (McKenna et al, 2008). DNA repair and DNA damage checkpoint were intact in the absence of SNF5, with no genomic alterations observed in the primary SNF5-deficient malignant rhabdoid tumors (McKenna et al, 2008).…”

“…Some reports have shown that this complex is recruited to the site of DSBs, and inactivation of this complex leads to inefficient DSB repair, leading to genomic instability (Chai et al, 2005;Vries et al, 2005;Klochendler-Yeivin et al, 2006;Park et al, 2006). However, another report showed that loss of SNF5 does not affect the sensitivity to DNA damaging agents, g-H2AX induction and their recruitment to sites of DNA damage, and that neither BRG1 nor SNF5 colocalizes with g-H2AX foci (McKenna et al, 2008). DNA repair and DNA damage checkpoint were intact in the absence of SNF5, with no genomic alterations observed in the primary SNF5-deficient malignant rhabdoid tumors (McKenna et al, 2008).…”

Analysis of Prognostic Marker Panel for High-Grade Serous Ovarian Cancer through Age-Dependent DNA Methylation

“…Promoter methylation can be seen as an alternative gene-inactivation mechanism to chromosomal loss and loss of functional mutations [38]. Both genetic (changes in DNA sequence, such as deletions/amplifications and mutations) and epigenetic changes can be defined as heritable changes in gene expression that occur without changes to the DNA sequence [39]. In contrast to DNA sequence changes, chromosomal loss and mutations are essentially irreversible.…”