Cancer and the bromodomains of BAF180

Brownlee, Peter M.; Chambers, A.; Oliver, Antony W.; Downs, Jessica A.

doi:10.1042/bst20110754

Cited by 33 publications

(36 citation statements)

References 28 publications

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“…BRG1, BRM, and particularly the non-ATPase components of the SWI/SNF complexes are frequently inactivated in multiple cancers (26,30,31,36,37). Thus, the SWI/SNF complex has long been regarded as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

BRG1 and BRM Chromatin-Remodeling Complexes Regulate the Hypoxia Response by Acting as Coactivators for a Subset of Hypoxia-Inducible Transcription Factor Target Genes

Sena¹,

Wang

2013

Molecular and Cellular Biology

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Chromatin remodeling is an active process, which represses or enables the access of transcription machinery to genes in response to external stimuli, including hypoxia. However, in hypoxia, the specific requirement, as well as the molecular mechanism by which the chromatin-remodeling complexes regulate gene expression, remains unclear. In this study, we report that the Brahma (BRM) and Brahma-related gene 1 (BRG1) ATPase-containing SWI/SNF chromatin-remodeling complexes promote the expression of the hypoxia-inducible transcription factor 1␣ (HIF1␣) and HIF2␣ genes and also promote hypoxic induction of a subset of HIF1 and HIF2 target genes. We show that BRG1 or BRM knockdown in Hep3B and RCC4T cells reduces hypoxic induction of HIF target genes, while reexpression of BRG1 or BRM in BRG1/BRM-deficient SW13 cells increases HIF target gene activation. Mechanistically, HIF1 and HIF2 increase the hypoxic induction of HIF target genes by recruiting BRG1 complexes to HIF target gene promoters, which promotes nucleosome remodeling of HIF target gene promoters in a BRG1 ATPase-dependent manner. Importantly, we found that the function of BRG1 complexes in hypoxic SW13 and RCC4T cells is dictated by the HIF-mediated hypoxia response and could be opposite from their function in normoxic SW13 and RCC4T cells.H ypoxia (Hx) is a common characteristic of many solid tumors. The Hx intratumoral microenvironment stabilizes hypoxia-inducible transcription factor 1␣ (HIF1␣) and HIF2␣, which are normally degraded under normoxia (Nx). The stabilized HIF1␣ and HIF2␣ proteins translocate to the nucleus, where they dimerize with the constitutive nuclear protein ARNT (the aryl hydrocarbon receptor nuclear translocator, also called HIF1␤) to form HIF1␣/ARNT (HIF1) and HIF2␣/ARNT (HIF2) heterodimers. HIF1 and HIF2 bind to HIF binding sites (HBS) on HIF target gene promoters and/or enhancers and transactivate genes involved in neovascularization, glycolysis, cellular proliferation, and metastasis. Thus, the HIF-mediated Hx transcriptional response is critical for tumor progression by allowing cancer cells to adapt to a low-oxygen environment (1-4). However, recent reports indicate that the HIF2-and particularly the HIF1-mediated Hx response can activate tumor-suppressive genes, such as Scgb3a, Bnip3, Bnip3L, Nix, MYC inhibitor Mxi, p21, and p27, in a cell-type-specific manner (5-10).It is well established that multiple transcription factors (TFs) are required to achieve maximal activation of target genes in response to a specific stimulus such as Hx. This multifactorial transcription complex has been termed the "enhanceosome." Individual TFs in the enhanceosome complex may promote transcription by recruiting RNA polymerase II/general TFs and/or by recruiting chromatin-modifying enzymes such as histone acetylase, CBP and p300, and the chromatin-remodeling SWI/SNF complex. In the context of the enhanceosome associated with the Hx response, two additional TFs, STAT3 and USF2, are required for maximal Hx response (11,12). STAT3 and USF2 function...

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Section: Discussionmentioning

confidence: 99%

BRG1 and BRM Chromatin-Remodeling Complexes Regulate the Hypoxia Response by Acting as Coactivators for a Subset of Hypoxia-Inducible Transcription Factor Target Genes

Sena¹,

Wang

2013

Molecular and Cellular Biology

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“…Bromodomains are made up of ~100 amino acids and bind lysine residues modified by acetylation. 30 Histones have extensions (referred to as tails) with lysine (and other) residues that are enzymatically modified. 27 Bromodomains recognize acetylated lysine residues on histone tails, and, in vitro , each bromodomain of BAF180 has a distinct pattern of affinity for acetylated peptides.…”

Section: Pbrm1 Encodes Baf180 a Subunit Of A Nucleosome Remodeling Cmentioning

confidence: 99%

“…27 Bromodomains recognize acetylated lysine residues on histone tails, and, in vitro , each bromodomain of BAF180 has a distinct pattern of affinity for acetylated peptides. 30–33 Overall, the affinity of each bromodomain for each peptide is low, and BAF180 may bind cooperatively to a precise pattern of acetylated lysine residues in nucleosomes. 33 This process would bring the PBAF complex to a specific region of DNA where nucleosome remodeling would occur.…”

Section: Pbrm1 Encodes Baf180 a Subunit Of A Nucleosome Remodeling Cmentioning

confidence: 99%

PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma

Brugarolas

2013

The Cancer Journal

104

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Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer. Hitherto, one gene was known to be frequently mutated in renal cell carcinoma of clear cell type (ccRCC), the von Hippel-Lindau (VHL) gene. VHL was identified by positional cloning as the gene responsible for a familial syndrome with renal cancer predisposition, von Hippel-Lindau. Subsequently, VHL was found to be inactivated in approximately 90% of sporadic ccRCC. The discovery of VHL, together with the elucidation of its function, transformed the treatment of ccRCC leading to the introduction of 5 new drugs into the clinic. However, no other familial RCC predisposing genes are frequently mutated in sporadic ccRCC. With the development of massively parallel sequencing, a plethora of somatically mutated genes have been identified. Most genes are mutated at low frequencies, but three genes are mutated in >10% of ccRCC, PBRM1 (mutated in ~50%), BAP1 (~15%) and SETD2 (~15%). Like VHL, all 3 genes are two-hit tumor suppressor genes. Furthermore, these 3 genes are within a 50 Mb region on the short arm of chromosome 3p that encompasses VHL and is deleted in over 90% of ccRCC. We discovered that PBRM1 mutations tend to anti-correlate with BAP1 mutations in ccRCC, and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes. This established the foundation for the first molecular genetic classification of sporadic ccRCC. Herein, I review the evidence that implicated PBRM1 and BAP1 as renal cancer driver genes, provide an update on the function of the gene products, and speculate on how mutations in these genes may be exploited therapeutically.

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“…The ability to possess all types of nucleosome remodeling activities distinguishes it from other chromatin remodeling complexes [24]. The recent studies concerning the significance of SWI/SNF complex for the cell reprogramming and association of the SWI/SNF subunits mutations with cancer susceptibility have made this complex interesting for a wide circle of investigators [25] [26]. Figure 7.…”

Section: Discussionmentioning

confidence: 99%