SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

Bourgo, Ryan J.; Siddiqui, Hasan; Fox, Sejal R.; Solomon, David A.; Sansam, Courtney G.; Yaniv, Moshe; Muchardt, Christian; Metzger, Daniel; Chambon, Pierre; Roberts, Charles W.M.; Knudsen, Erik S.

doi:10.1091/mbc.e08-12-1224

Cited by 70 publications

(67 citation statements)

References 30 publications

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“…Knockout of BRG1 results in the dissolution of pericentromeric heterochromatin (33), suggesting that BRG1 plays a role in regulating heterochromatin structure. Therefore, we next sought to determine whether ectopic BRG1 is sufficient to drive SAHF formation.…”

Section: Resultsmentioning

confidence: 99%

BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

Zhuang

Yao

et al. 2013

Molecular and Cellular Biology

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bCellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of senescenceassociated heterochromatin foci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21 CIP1 , and p16 INK4a , but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.

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Section: Resultsmentioning

confidence: 99%

BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

Zhuang

Yao

et al. 2013

Molecular and Cellular Biology

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“…Overexpression of CENP-A has been linked to CIN in colon tumors and causes chromosome mis-segregation in colon cancer cells (Tomonaga et al, 2003;Amato et al, 2009). In model organisms, disruption of the pathways which maintain pericentromeric heterochromatin has been linked to chromosome mis-segregation and cancer (Bernard et al, 2001;Peters et al, 2001;David et al, 2003;David et al, 2006;Bourgo et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Potential candidates include mis-expression of the SUV39H1/2 methyltransferases whose inactivation in mice eliminates pericentromeric H3K9me3 and drives CIN, and tumorigenesis (Peters et al, 2001). In addition, pRb, one of the most frequently mutated genes in human cancer, as well as the chromatin remodeling complexes SWI/SNF and mSds3, are all required for faithful chromosome segregation and tumor suppression and have been implicated in the maintenance of pericentromeric heterochromatin and H3K9 methylation (David et al, 2003;Gonzalo et al, 2005;David et al, 2006;Bourgo et al, 2009;Sullivan et al, 2011).…”

Section: Pericentromeric Heterochromatin Changes In Cancer Rb Slee Et Almentioning

confidence: 99%

“…The function of the centromere is therefore vulnerable to disruption of the pathways that maintain this unique chromatin architecture. CENP-A overexpression is seen in breast and colon cancer and has been linked to a CIN phenotype (Perou et al, 2000;Tomonaga et al, 2003;Amato et al, 2009), and engineered disruption of pericentromeric heterochromatin is associated with chromosome mis-segregation and tumorigenesis (Ekwall et al, 1997;Bernard et al, 2001;Peters et al, 2001;David et al, 2003;Shin et al, 2003;Gonzalo et al, 2005;David et al, 2006;Bourgo et al, 2009). Furthermore, targeting of chromatin modifiers to human artificial chromosomes disrupts centromere function (Nakano et al, 2008;Cardinale et al, 2009;Bergmann et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

et al. 2011

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Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP-PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP-PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.

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“…However, little is known about their role in pancreatic cancer. The SWI/SNF complexes are large, multi-subunit complexes containing 10 or more subunits, serving as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control (21). Each complex has one of the two different ATPase as core motor; BRM or BRG1, and subunits which are referred to as BAFs (BRM-or BRG1-associated factors).…”

Section: Discussionmentioning

confidence: 99%

The clinical significance of SWI/SNF complex in pancreatic cancer.

Numata

Morinaga

Watanabe

et al. 2013

JCO

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Abstract. Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study was to clarify the clinical significance of the SWItch/sucrose nonfermentable (SWI/SNF) complex in patients with pancreatic cancer. A total of 68 patients with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180 and BAF47. The correlation of expression levels and clinicopathological outcomes were analyzed, followed by the multivariate analysis of prognostic factors for overall survival. The expression levels of the SWI/SNF components were categorized as low or high according to the median value of Histoscore. Statistical analysis revealed that BRM expression was related to tumor size, T factor, M factor, lymphatic invasion and stage BRG1 expression to histology and stage BAF180 expression to tumor size and BAF47 expression to lymphatic invasion, respectively. Multivariate Cox proportional hazard analysis showed that high BRM and low BAF180 expression levels were independent predictors of worse survival in patients with pancreatic cancer. High BRM, and low BAF180 were also independent prognostic factors for poor survival in the subgroup with adjuvant gemcitabine. These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High BRM, and low BAF180 are useful biomarkers for poor prognosis in pancreatic cancer. IntroductionPancreatic cancer remains a leading cause of cancer deaths in the advanced nation (1,2). The overall 5-year survival rate is reported to be less than 5% (3). A reliable and clinically relevant prognostic biomarker which can stratify the disease is needed for developing new strategies.It is a known fact that chromatin, highly condensed and dynamically structured, can be temporally rearranged so that specific genes can be expressed or repressed (4). Studies have shown that modification of chromatin structure is an essential step in gene regulation primarily mediated by chromatin remodeling proteins. Among these proteins, histone is known to play a dynamic role in the regulation of transcription (5-7). Often, transcription is also regulated by other cofactors, and the balance of chromatin remodeling activities may be crucial to ensure accurate responses to developmental or environmental cues and to prevent the transition of normal cells into cancer cells (8).The SWItch/sucrose non-fermentable (SWI/SNF) complex is a major complex of adenosine triphosphate (ATP)-dependent chromatin remodeling factors and controls the transcriptional activity of a variety of genes involved in cellular growth and transformation by altering chromatin structure (9-13). SWI/ SNF complex, originally identified in yeast, is composed of more than 10 characterized subunits (14,15) and human SWI/ SNF complexes con...

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SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

Cited by 70 publications

References 30 publications

BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability

The clinical significance of SWI/SNF complex in pancreatic cancer.

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