Abstract
Simple SummaryMammalian SWI/SNF complexes regulate gene expression by reorganizing the way DNA is packaged into chromatin. SWI/SNF subunits are recurrently altered in tumors at multiple levels, including DNA mutations as well as alteration of the levels of RNA and protein. Cancer cell lines are often used to study SWI/SNF function, but their patterns of SWI/SNF alterations can be complex. Here, we present a comprehensive characterization of DNA mutations and RNA and protein expression of SWI/SNF members in 38 lung adenocarcinoma (LUAD) cell lines. We show that over 85% of our cell lines harbored at least one alteration in one SWI/SNF subunit. In addition, over 75% of our cell lines lacked expression of at least one SWI/SNF subunit at the protein level. Our catalog will help researchers choose an appropriate cell line model to study SWI/SNF function in LUAD.Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.
Highlights
Advances in DNA sequencing technologies have helped in deciphering the mutational landscape of human cancers
We selected a panel of representative lung adenocarcinoma (LUAD) cell lines that are commonly used and that combine different genetic and clinical backgrounds
Subunits that were detected in a SMARCA4 immunoprecipitation in a non-tumor lung cell line (Peinado, P. et al [27], Manuscript in preparation) and the top five LUAD driver genes identified by Bailey and colleagues [22] using capture-based DNA sequencing
Summary
Advances in DNA sequencing technologies have helped in deciphering the mutational landscape of human cancers. In vitro models are extensively used in bench research because they allow researchers to test new hypotheses in simple but clinically translatable experiments In this way, in vitro models are often the first step for studies that aim to improve the diagnosis, the prognosis, or the treatment of diseases. We focus on the multiprotein complex SWI/SNF (SWitch/Sucrose Non-Fermentable), which is an ATP-dependent chromatin-remodeling complex that controls nucleosome positioning and recruits other chromatin binding factors. This complex has been considered as the most mutated chromatin regulator and one of the most mutated tumor suppressors with alterations found in almost 20% of all human neoplasias [3,4]. Many researchers are studying this complex and looking for new strategies to treat SWI/SNF-mutant tumors
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