BRG1 Cancer as an Epigenetic Disease By: Emily Zuehlke Source: UniProt

General role Cancers it’s involved in Where it is BRG1 and the SWI/SNF Remodeling Complex Early embryonic developmentDifferentiation of neuronal cellsZygotic Genome Activation Proliferation of lymphocytesProliferation of blood vessel cellsDifferentiation of cardiac cells Source: Cancer 2006

The SWI/SNF complex remodels chromatin Source: Cancer 2006

The SWI/SNF complex causes the nucleosome to slide or to be ejected from the chromatin This exposes the DNA and allows for transcription factors to bind Source: Cancer 2011

BRG1 and the SWI/SNF complex regulate epigenetics in numerous pathways Source: Cancer 2011

Conditional knock-outs reveal BRG1’s conserved presence and varied roles in test species Source: Kopp, Nature 2003.Source: Marenda, Dev Bio 2004

Combinatorial assembly results in BRG1’s role in various key cellular functions Source: Ho, Nature 2010

Missense mutations can abolish BRG1’s ATPase activity Source: Medina, Epigenetics 2008 Source: Wong, Cancer Research 2000

BRG1 is implicated as a tumor suppressor and an oncogene in numerous cancers Non-small cell lung cancer Oral Squamous Cell Carcinoma MelanomaColon Cancer Prevalence of mutation/delet ion 35%57%38-79%ND Stage 1, 5 yr Prognosis 45-49%50%92-97%74% Treatment Lobectomy, pneumo- nectomy, chemotherapy Radiation therapy, surgical excision, glossectomy Excisional biopsies, sentinel lymph node biopsy Polypectomy, colectomy, chemotherapy BRG1 acts as… Tumor Suppressor OncogeneOncogene or tumor suppressor Sources: Sanchez-Cespedes, EMBO 2012; Lin, BJD 2010; Wikipedia

BRG1 mutations are involved in one-third of non-small cell lung cancers Source: Reisman, Cancer Research 2003

BRG1 has potential as a drug target in some cancer lines Source: Lin, BJD 2010

Smoking may increase susceptibility to mutations in BRG1 Sources: Medina, 2008; Matsuda, 1998

Sources Copp, Andrew J, Nicholas DE Green, and Jennifer N Murdoch. The Genetic Basis of Mammalian Neurulation. Nature Reviews Genetics , ; Glaros, Selina, et al. Targeted Knockout of BRG1 Potentiates Lung Cancer Development. Cancer Research :10, ; Gunduz, Esra, et al. Frequent Deletion of BRG1 Locus at 19p13 Predicts Recurrence and Previous Cancer History in Oral Squamous Cell Carcinomas. Journal of Hard Tissue Biology :1, 20-26; Lin, H., et al. BRG1 expression is increased in human cutaneous melanoma. British Journal of Dermatology :3, Ho, Lena, and Gerald R. Crabtree. Chromatin Remodeling during development. Nature , ; Marenda, Daniel R, Claudia B Zraly, and Andrew K Dingwall. The Drosophila Brahma chromatin remodeling complex exhibits cell-type specific activation and repression functions. Developmental Biology :2, ; Matsuda, Tomonari, et al. Specific tandem GG to TT base substitutions induced by acetaldehyde are due to intra-strand crosslinks between adjacent guanine bases. Nucleic Acids Resarch 1998; 26:7, ; Medina P, Sanchez-Cespedes M. Involvement of the chromatin-remodeling factor BRG1/SMARCA4 in human cancer. Epigenetics 2008; 3: ; PMID: ; Reisman, David, Janiece Sciarrotta, and Weidong Wang, et al. Loss of BRG1/BRM in Human Lung Cancer Cell Lines and Primary Lung Cancers: Correlation with Poor Prognosis. Cancer Research , ; Rodriguez-Nieto, Salvador, and Monse Sanchez-Cespedes. BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer. Carcinogenesis :4, ; Sanchez-Cespedes, Montse, et al. BRG1 Mutations Confer Resistance to Hormones in Lung Cancer. EMBO Molecular Medicine 2012; Wilson, Boris G and Charles WM Roberts. SWI/SNF nucleosome remodellers and cancer. Nature Reviews Wong, Alexander KC et al. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Research , ; Wu, Jian I. Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer. Dept. of Physiology and Developmental Biology, University of Texas Southwest Medical Center at Dallas, TX, 2012.