BRG1 loss in MiaPaCa2 cells induces an altered cellular morphology and disruption in the organization of the actin cytoskeleton.
BRG1 and Brahma are critical and mutually exclusive subunits of the multi-constituent SWI/SNF chromatin remodeling complexes. These complexes play a key role in transcriptional regulation by dynamically altering chromatin architecture. Although the two proteins are very similar in structure, murine models demonstrate a clear dichotomy in BRG1/BRM function as heterozygous loss of BRG1 results in tumor development whereas homozygous loss of BRM does not. BRG1 and/or BRM protein is absent or disrupted in approximately 17% of all human adenocarcinomas. Concomitant loss is frequent in non-small cell lung carcinomas and incurs a negative prognosis. The mechanism(s) whereby loss of BRG1 (but apparently not BRM) may contribute to tumor development and/or progression is/are ill defined. In this study, we employ MiaPaCa2, a human pancreatic adenocarcinoma cell line that lacks BRM but retains BRG1 expression to evaluate the impact of BRG1 and BRM individually on growth and tumorigenicity. We show that the MiaPaca2 cell line can apparently tolerate only very low levels of BRM after restoration of stable expression. Reduction of expression of BRG1 via shRNAi in stable clones of MiaPaCa2 results in a marked change in morphology and alterations in actin cytoskeletal organization but does not appear to exert a significant effect on in vitro growth of the cell line. Our results implicate a role for the SWI/SNF complex in the regulation of cellular differentiation.
Rosson
Gary B
GB
Department of Pathology and Laboratory Medicine, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
Bartlett
Christopher
C
Reed
William
W
Weissman
B E
BE
D000199:Actins / Q000378:metabolism*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D004265:DNA Helicases; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D000199:Actins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases