Inactivation of chromatin remodeling factors sensitizes cells to selective cytotoxic stress

Abstract

The SWI/SNF chromatin-remodeling complex plays an essential role in several cellular processes including cell proliferation, differentiation, and DNA repair. Loss of normal function of the SWI/SNF complex because of mutations in its subunits correlates with tumorigenesis in humans. For many of these cancers, cytotoxic chemotherapy is the primary, and sometimes the only, therapeutic alternative. Among the antineoplastic agents, anthracyclines are a common treatment option. Although effective, resistance to these agents usually develops and serious dose-related toxicity, namely, chronic cardiotoxicity, limits its use. Previous work from our laboratory showed that a deletion of the SWI/SNF factor SNF2 resulted in hypersensitivity to doxorubicin. We further investigated the contribution of other chromatin remodeling complex components in the response to cytotoxic chemotherapy. Our results indicate that, of the eight SWI/SNF strains tested, snf2, taf14, and swi3 were the most sensitive and displayed distinct sensitivity to different cytotoxic agents, while snf5 displayed resistance. Our experimental results indicate that the SWI/SNF complex plays a critical role in protecting cells from exposure to cytotoxic chemotherapy and other cytotoxic agents. Our findings may prove useful in the development of a strategy aimed at targeting these genes to provide an alternative by hypersensitizing cancer cells to chemotherapeutic agents.

BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors

“…Mutations in various subunits of the SWI/SNF complex sensitize for chemotherapy with doxorubicin and cisplatin in yeast [ 51 ]. In contrast, mutations in SNF5, the yeast homolog of SMARCB1, resulted in reduced sensitivity to doxorubicin [ 52 ]. According to our results, BRD9i treatment sensitizes RT cell lines to doxorubicin.…”

Combined Antibody/Lectin Enrichment Identifies Extensive Changes in the O-GlcNAc Sub-proteome upon Oxidative Stress

“…As discussed below, these data implicate O- GlcNAc in mediating transcription and translation as well as protein folding. The induction of cellular injury results in widespread changes in transcriptional patterns, many of which require ATP-dependent chromatin remodelers that act as both transcription co-repressors and activators. − Highlighting the importance of chromatin remodelers, deletion of one or more components of these complexes can sensitize cells to injury and can impact the ability of heat shock factor 1 (HSF1) to induce the expression of the canonical chaperones or HSPs . Numerous proteins that are components of the BAF and pBAF SWI/SNF chromatin remodeling complexes were identified in the G5-lectibody immuno­precipitate, including SmarcA5/snf2h, Smarcb1/Baf47, Smarcc2/Baf170, Smarcc1/Baf155, SmarcD1/Baf60a, SmarcD2/Baf60b, SmarcD3/Baf60c, Smarce1/Baf57, Arid1b/Baf250a, Pbrm1/Baf180, ep400/Domino, Dmap1/Mmtr, and Trrap. − AT-rich interactive domain-containing protein 1A (Arid1A) demonstrated a robust change in O- GlcN­Acylation, with a 2.15- and 2.52-fold increases after 1 and 2 h of oxidative stress, respectively.…”

Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response

“…HR repair-deficient cancer cells (here due to BAP1 loss) are not capable of repairing the massive DNA damage caused by chemotherapy and will in most cases undergo cell death. In addition, PBRM1 loss could further increase sensitivity, because BAF180 (encoded by PBRM1 ) as part of the SWI/SNF complex might play a critical role in protecting DNA from damage (Freeman et al 2014). The majority of mesothelioma patients harbor BAP1 alterations with heterozygous loss being detected in about 30%–60% of cases (Bott et al 2011; Borczuk et al 2016; Joseph et al 2017; Leblay et al 2017; Hmeljak et al 2018), whereas homozygous deletion seem to be a rare event in peritoneal mesothelioma and infrequent also in pleural mesothelioma (which is far more extensively studied).…”