Alteration to the SWI/SNF complex in human cancers

Gordon, Vanessa S.; Rogers, C.; Reisman, David

doi:10.4081/oncol.2010.89

Cited by 3 publications

(8 citation statements)

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“…76 This complex regulation of BRM likely stems from the multitude of cellular processes with which BRM and SWI/SNF are involved, particularly growth control, differentiation and development. 3,4 It is unclear why BRM is sometimes inactivated by acetylation while in other instances it is silenced by suppression. Interestingly, the MAP kinase pathway is able to induce BRM silencing and in other cases, BRM acetylation.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 This complex has since been shown to have a role in human gene expression, where it associates with and is required for the function of a diverse array of key cellular proteins and transcription factors (TFs), many of which have important roles in cancer development. 3,4 The SWI/ SNF complex remodels chromatin such that regions and domains of DNA are made more accessible to cellular proteins that promote gene expression. [5][6][7] SWI/SNF therefore serves a catalytic role in facilitating and promoting gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…As a result of the large number of cellular proteins that are functionally linked to this complex, it is not surprising that this complex is frequently targeted and disrupted during cancer development. SWI/SNF has been linked to growth control, DNA repair, differentiation, development and cellular adhesion, and when SWI/SNF is rendered nonfunctional or impaired, these processes are also negatively impacted 3,4 potentially promoting cancer development and progression.…”

Section: Introductionmentioning

confidence: 99%

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Identifying targets for the restoration and reactivation of BRM

et al. 2013

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Brahma (BRM) is a novel anticancer gene, which is frequently inactivated in a variety of tumor types. Unlike many anticancer genes, BRM is not mutated, but rather epigenetically silenced. In addition, histone deacetylase complex (HDAC) inhibitors are known to reverse BRM silencing, but they also inactivate it via acetylation of its C-terminus. High-throughput screening has uncovered many compounds that are effective at pharmacologically restoring BRM and thereby inhibit cancer cell growth. As we do not know which specific proteins, if any, regulate BRM, we sought to identify the proteins, which underlie the epigenetic suppression of BRM. By selectively knocking down each HDAC, we found that HDAC3 and HDAC9 regulate BRM expression, whereas HDAC2 controls its acetylation. Similarly, we ectopically overexpressed 21 different histone acetyltransferases and found that KAT6A, KAT6B and KAT7 induce BRM expression, whereas KAT2B and KAT8 induce its acetylation. We also investigated the role of two transcription factors (TFs) linked to either BRM (GATA3) or HDAC9 (MEF2D) expression. Knockdown of either GATA3 and/or MEF2D downregulated HDAC9 and induced BRM. As targets for molecular biotherapy are typically uniquely, or simply differentially expressed in cancer cells, we also determined if any of these proteins are dysregulated. However, by sequencing, no mutations were found in any of these BRM-regulating HDACs, HATs or TFs. We selectively knocked down GATA3, MEF2D, HDAC3 and HDAC9, and found that each gene-specific knockdown induced growth inhibition. We observed that both GATA3 and HDAC9 were greatly overexpressed only in BRM-negative cell lines indicating that HDAC9 may be a good target for therapy. We also found that the mitogen-activated protein (MAP) kinase pathway regulates both BRM acetylation and BRM silencing as MAP kinase pathway inhibitors both induced BRM as well as caused BRM deacetylation. Together, these data identify a cadre of key proteins, which underlie the epigenetic regulation of BRM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identifying targets for the restoration and reactivation of BRM

et al. 2013

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“…SWI/SNF and BRM are known to regulate cellular adhesion, DNA repair, differentiation, and expression of MHC class 1 and 2 proteins ( 2 ). Hence, while their suppression in certain circumstances might promote growth inhibition, it is equally possible such a strategy could have adverse clinical consequences by accelerating de-differentiation and promoting metastasis by inhibiting the expression of adhesion proteins such as E-cadherin, CEACAM1, integrins, and CD44, which are known to be regulated by SWI/SNF ( 2 , 25 ). Moreover, the loss of both BRG1 and BRM would favor the inhibition of DNA repair ( 2 , 25 ), and in particular, such key DNA repair genes as GADD45 ( 26 ), which in turn could enhance tumor progression.…”

Section: Synthetic Lethality and The Clinical Silencing Of mentioning

confidence: 99%

“…Hence, while their suppression in certain circumstances might promote growth inhibition, it is equally possible such a strategy could have adverse clinical consequences by accelerating de-differentiation and promoting metastasis by inhibiting the expression of adhesion proteins such as E-cadherin, CEACAM1, integrins, and CD44, which are known to be regulated by SWI/SNF ( 2 , 25 ). Moreover, the loss of both BRG1 and BRM would favor the inhibition of DNA repair ( 2 , 25 ), and in particular, such key DNA repair genes as GADD45 ( 26 ), which in turn could enhance tumor progression. As SWI/SNF is reported to regulate MHC class 1 and 2 proteins ( 27 – 29 ), the silencing of BRM might result in the loss of these proteins, impairing the normal function of the immune system ( 30 ).…”

Section: Synthetic Lethality and The Clinical Silencing Of mentioning

confidence: 99%

Beyond Mutations: Additional Mechanisms and Implications of SWI/SNF Complex Inactivation

et al. 2015

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† Denotes Co-First Author as each person contributed equally to this manuscript.SWI/SNF is a major regulator of gene expression. Its role is to facilitate the shifting and exposure of DNA segments within the promoter and other key domains to transcription factors and other essential cellular proteins. This complex interacts with a wide range of proteins and does not function within a single, specific pathway; thus, it is involved in a multitude of cellular processes, including DNA repair, differentiation, development, cell adhesion, and growth control. Given SWI/SNF's prominent role in these processes, many of which are important for blocking cancer development, it is not surprising that the SWI/SNF complex is targeted during cancer initiation and progression both by mutations and by non-mutational mechanisms. Currently, the understanding of the types of alterations, their frequency, and their impact on the SWI/SNF subunits is an area of intense research that has been bolstered by a recent cadre of NextGen sequencing studies. These studies have revealed mutations in SWI/SNF subunits, indicating that this complex is thus important for cancer development. The purpose of this review is to put into perspective the role of mutations versus other mechanisms in the silencing of SWI/SNF subunits, in particular, BRG1 and BRM. In addition, this review explores the recent development of synthetic lethality and how it applies to this complex, as well as how BRM polymorphisms are becoming recognized as potential clinical biomarkers for cancer risk. Significance: Recent reviews have detailed the occurrence of mutations in nearly all SWI/SNF subunits, which indicates that this complex is an important target for cancer. However, when the frequency of mutations in a given tumor type is compared to the frequency of subunit loss, it becomes clear that other non-mutational mechanisms must play a role in the inactivation of SWI/SNF subunits. Such data indicate that epigenetic mechanisms that are known to regulate BRM may also be involved in the loss of expression of other SWI/SNF subunits. This is important since epigenetically silenced genes are inducible, and thus, the reversal of the silencing of these non-mutationally suppressed subunits may be a viable mode of targeted therapy.

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Mechanism of BRG1 silencing in primary cancers

et al. 2016

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BRG1 (SMARCA4) is a documented tumor suppressor and a key subunit of the SWI/SNF chromatin remodeling complex that is silenced in many cancer types. Studies have shown that BRG1 is mutated in cancer-derived cell lines, which led to the assertion that BRG1 is also mutated in primary human tumors. However, the sequencing of BRG1-deficient tumors has revealed a paucity of mutations; hence, the cause of BRG1 silencing in tumors remains an enigma. We conducted immunohistochemistry (IHC) on a number of tumor microarrays to characterize the frequency of BRG1 loss in different tumor types. We also analyzed BRG1-deficient tumors by sequencing the genomic DNA and the mRNA. We then tested if BRG1 expression could be induced in BRG1-negative cell lines (i.e., that lack mutations in BRG1) after the application of several different epigenetic agents, including drugs that inhibit the AKT pathway. We found that a subset of BRG1-negative cell lines also demonstrated aberrant splicing of BRG1, and in at least 30% of BRG1-deficient tumors, BRG1 expression appeared to be suppressed due to aberrant BRG1 splicing.As the majority of BRG1-deficient tumors lack mutations or splicing defects that could drive BRG1 loss of expression, this suggests that other mechanisms underlie BRG1 silencing. To this end, we analyzed 3 BRG1-deficient nonmutated cancer cell lines and found that BRG1 was inducible in these cell lines upon inhibition of the AKT pathway. We show that the loss of BRG1 is associated with the loss of E-cadherin and up-regulation of Vimentin in primary tumors, which explains why BRG1 loss is associated with a poor prognosis in multiple tumor types.

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Alteration to the SWI/SNF complex in human cancers

Cited by 3 publications

References 0 publications

Identifying targets for the restoration and reactivation of BRM

Identifying targets for the restoration and reactivation of BRM

Beyond Mutations: Additional Mechanisms and Implications of SWI/SNF Complex Inactivation

Mechanism of BRG1 silencing in primary cancers

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