Abstract 2081: Transcriptional silencing of CDK18 in BRG1 mutant lung cancer

Abstract

Abstract In ~10% of lung cancers, the BRG1 gene is mutated often causing a loss of function (LOF). BRG1 is a tumor suppressor that encodes a protein (SMARCA4), which is one of the mutually exclusive ATPase subunits of the Switch/Sucrose Non-fermentable (SWI/SNF) complex. The SWI/SNF complex functions to regulate transcription of many genes including tumor suppressor genes, through mediating chromatin remodeling and nucleosome repositioning by maintaining open chromatin and actively evicting polycomb repressive complexes (PRCs) from target genes and regions. Our previous research showed that BRG1 mutation occurs in approximately 9% of lung adenocarcinomas in smokers and 11% in smokers delineating BRG1 as a clinically relevant mutation. The goal of these studies is to elucidate the downstream effects of BRG1 LOF on gene expression. RNA sequencing of isogenic BRG1 wild type (WT) and knock out (KO) clones from malignant and transformed cell lines identified cell cycle control and chromosomal replication as the most significantly affected pathway. qRT-PCR was used to validate expression changes in 17 genes from this pathway in the WT and KO clones as well as wild type and mutant tumors lines. CDK18 was the most significantly affected target exhibiting a 78% reduction in expression (p<0.001) comparing wild type to mutant cell lines. Ongoing studies are investigating the epigenetic mechanisms leading to transcriptional repression of CDK18 that include cytosine DNA methylation and histone methylation of H3K27. In addition, functional assays (e.g., soft agar, cell migration) are evaluating the role of epigenetically repressed CDK18 in lung carcinogenesis and cell cycle control through siRNA knock down of CDK18 in wild type BRG1 cell lines and carcinogen transformed human bronchial epithelial cells. Together, these studies will provide new insight into the role of LOF of CDK18 in BRG1 mutant cancer. (Supported by P30 CA11800). Citation Format: Loryn Michelle Phillips, Christopher A. Johnston, Steven A. Belinsky, Mathewos Tessema. Transcriptional silencing of CDK18 in BRG1 mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2081.