Abstract 3930: Integrative genomic analysis reveals SWI/SNF chromatin remodeling complex to be a TGFβ-mediating tumor suppressor pathway in pancreatic cancer

Author(s):  
Alan H. Shain ◽  
Karen Matsukuma ◽  
Craig Giacomini ◽  
Collins A. Karikari ◽  
Manuel Hidalgo ◽  
...  
2009 ◽  
Vol 69 (20) ◽  
pp. 8094-8101 ◽  
Author(s):  
Xi Wang ◽  
Courtney G. Sansam ◽  
Christopher S. Thom ◽  
Daniel Metzger ◽  
Julia A. Evans ◽  
...  

2008 ◽  
Vol 28 (20) ◽  
pp. 6223-6233 ◽  
Author(s):  
Elizabeth S. McKenna ◽  
Courtney G. Sansam ◽  
Yoon-Jae Cho ◽  
Heidi Greulich ◽  
Julia A. Evans ◽  
...  

ABSTRACT There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in γ-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.


2013 ◽  
Vol 35 (3) ◽  
pp. 255-261 ◽  
Author(s):  
Xiao-Qiang GUO ◽  
Qiao-Xia ZHANG ◽  
Wei-Ren HUANG ◽  
Xiang-Lin DUAN ◽  
Zhi-Ming CAI

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 520
Author(s):  
Wenfeng Nie ◽  
Jinyu Wang

As essential structural components of ATP-dependent chromatin-remodeling complex, the nucleolus-localized actin-related proteins (ARPs) play critical roles in many biological processes. Among them, ARP4 is identified as an integral subunit of chromatin remodeling complex SWR1, which is conserved in yeast, humans and plants. It was shown that RNAi mediated knock-down of Arabidopsis thaliana ARP4 (AtARP4) could affect plant development, specifically, leading to early flowering. However, so far, little is known about how ARP4 functions in the SWR1 complex in plant. Here, we identified a loss-of-function mutant of AtARP4 with a single nucleotide change from glycine to arginine, which had significantly smaller leaf size. The results from the split luciferase complementation imaging (LCI) and yeast two hybrid (Y2H) assays confirmed its physical interaction with the scaffold and catalytic subunit of SWR1 complex, photoperiod-independent early flowering 1 (PIE1). Furthermore, mutation of AtARP4 caused altered transcription response of hundreds of genes, in which the number of up-regulated differentially expressed genes (DEGs) was much larger than those down-regulated. Although most DEGs in atarp4 are related to plant defense and response to hormones such as salicylic acid, overall, it has less overlapping with other swr1 mutants and the hta9 hta11 double-mutant. In conclusion, our results reveal that AtARP4 is important for plant growth and such an effect is likely attributed to its repression on gene expression, typically at defense-related loci, thus providing some evidence for the coordination of plant growth and defense, while the regulatory patterns and mechanisms are distinctive from other SWR1 complex components.


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