BRG1Cancer 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 development Differentiation of neuronal cellsZygotic Genome Activation

Proliferation of lymphocytes Proliferation 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 cancersNon-small cell

lung cancerOral Squamous Cell Carcinoma

Melanoma Colon Cancer

Prevalence of mutation/deletion

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

Tumor Suppressor

Oncogene Oncogene 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

2003. 4, 784-794; http://www.readcube.com/articles/10.1038/nrg1181• Glaros, Selina, et al. Targeted Knockout of BRG1 Potentiates Lung Cancer Development. Cancer Research 2006. 68:10, 3689-3696;

http://cancerres.aacrjournals.org/content/68/10/3689.full.pdf+html• 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 2006. 15:1, 20-26; http://www.htbiol.gr.jp/English/JHTB(pdf)/Vol.15(1)pdf/15_20.pdf• Lin, H., et al. BRG1 expression is increased in human cutaneous melanoma. British Journal of Dermatology 2010. 163:3, 502-510. • Ho, Lena, and Gerald R. Crabtree. Chromatin Remodeling during development. Nature 2010. 463, 474-484;

http://www.nature.com/nature/journal/v463/n7280/full/nature08911.html• 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 2004. 267:2, 279-293; http://www.sciencedirect.com/science/article/pii/S0012160603007309

• 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, 1769-1774; http://nar.oxfordjournals.org/content/26/7/1769.full.pdf+html

• Medina P, Sanchez-Cespedes M. Involvement of the chromatin-remodeling factor BRG1/SMARCA4 in human cancer. Epigenetics 2008; 3:64 - 68; PMID: 18437052; http://dx.doi.org10.4161/epi.3.2.6153.

• 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 2003. 63, 560-566; http://cancerres.aacrjournals.org/content/63/3/560.full.pdf

• Rodriguez-Nieto, Salvador, and Monse Sanchez-Cespedes. BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer. Carcinogenesis 2009. 30:4, 547-554; http://carcin.oxfordjournals.org/content/30/4/547.full

• Sanchez-Cespedes, Montse, et al. BRG1 Mutations Confer Resistance to Hormones in Lung Cancer. EMBO Molecular Medicine 2012; http://www.sciencenewsline.com/articles/2012031516130013.html

• Wilson, Boris G and Charles WM Roberts. SWI/SNF nucleosome remodellers and cancer. Nature Reviews 2011. 11. 481-492. http://www.nature.com/nrc/journal/v11/n7/full/nrc3068.html

• Wong, Alexander KC et al. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Research 2000. 60, 6171-6177; http://cancerres.aacrjournals.org/content/60/21/6171.full.pdf+html

• 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.