The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential

Yamamichi, Nobutake; Yamamichi-Nishina, Mitsue; Mizutani, Taketoshi; Watanabe, Hirotaka; Minoguchi, Shigeru; Kobayashi, Nao; Kimura, Susumu; Ito, Tsuyohito; Yahagi, Naohisa; Ichinose, Masakazu; Omata, Masao; Iba, Hideo

doi:10.1038/sj.onc.1208716

Cited by 96 publications

(97 citation statements)

References 38 publications

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“…This notion is supported by the finding that HDAC inhibitors can restore BRM expression in some cell lines (Bourachot et al, 2003;Yamamichi et al, 2005). To test this hypothesis, we treated our 10 cell lines that express very low or undetectable levels of BRM protein with butyrate, a broad-spectrum HDAC inhibitor.…”

Section: Resultsmentioning

confidence: 91%

“…Yet we also observed that after removing these compounds, BRM function was present, although transiently. Similarly, using MuLV virus gene expression as a marker, restoration of BRM function has been observed after removal of HDAC inhibitors (Yamamichi et al, 2005). HDAC inhibitors were not identified because of their ability to inhibit specific HDACs, but rather uncovered in various drug screens because of their ability to reverse malignant phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…The SWI/SNF complex and BRM are also required for differentiation and development (Simone, 2006). Loss of BRM has also been shown to impact cell migration and metastasis (Yamamichi et al, 2005). Given the potential importance of BRG1 and BRM loss in cancer development, we and others have sought to understand the mechanisms underlying how these proteins are silenced in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRMrelated gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

et al. 2007

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“…Unlike BRG1, experimental analysis by various groups has revealed that BRM is epigenetically silenced in 17 out of the 17 cell lines examined (Mizutani et al, 2002;Bourachot et al, 2003;Yamamichi et al, 2005;Glaros et al, 2007). The observation that BRM is epigenetically silenced in cancer, rather than mutated, suggests that it might be possible to restore BRM function in tumor cells.…”

Section: Brm Is Silenced By Epigenetic Mechanismsmentioning

confidence: 99%

“…Given that BRM is lost in B20% of a broad range of human cancers (Glaros et al, 2007), and that the introduction of BRM into BRM-deficient cell lines causes growth arrest Muchardt and Yaniv, 1999b;Bourachot et al, 2003), it is plausible that restoration of BRM expression might be clinically desirable. Several groups, including our own, have observed that histone deacetylase (HDAC) inhibitors can restore BRM mRNA and protein expression in a variety of BRM null cell lines (Mizutani et al, 2002;Bourachot et al, 2003;Yamamichi et al, 2005;Glaros et al, 2007). Nuclear run-on transcription assays were used by Yamamichi et al (2005) to show that BRM is strongly suppressed at the post-transcriptional level and that this suppression could be reversed by HDAC inhibitor treatment.…”

Section: Brm Is Silenced By Epigenetic Mechanismsmentioning

confidence: 99%

The SWI/SNF complex and cancer

2009

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The mammalian SWI/SNF complexes mediate ATPdependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).

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SWI / SNF Chromatin Remodelling and Human Cancer

Reisman

Thompson

Marquez-Vilendrer

et al. 2016

Encyclopedia of Life Sciences

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Brahma (BRM) and Brahma‐related gene 1 (BRG1) are two mutually exclusively catalytic subunits of the switch in mating type/sucrose nonfermenting complex. These two key anticancer proteins are frequently targeted and silenced during cancer development. The anticancer function of BRM can be abrogated when it becomes acetylated or when it is epigenetically silenced. Central to BRM silencing is the presence of two inherited insertional polymorphisms within the BRM promoter that are statistically linked to cancer risk. Both BRM acetylation and silencing can be reversed by a number of compound families and might be important to how flavonoids and NSAIDS inhibit cancer. While BRG1 is very frequently mutated in most human cancers, it is more commonly inactivated by aberrant splicing and by an AKT‐pathway‐mediated‐translation block. While BRG1 and BRM are tied to deoxyribonucleic acid repair, growth control, differentiation, development, as well as epithelial–mesenchymal transition and are estimated to regulate 4–8% of the human genome, the inactivation of either protein is only modestly tumourigenic. This occurs in part because BRG1 and BRM are functionally redundant, which blunts the tumourigenic effect when only one gene is aberrantly silenced. Further insights into the mechanisms that regulate these genes may lead to novel therapeutic strategies that may reverse the silencing of these two important anticancer genes. Key Concepts Reversal of the epigenetic silencing of a gene may serve as a basis for drug therapy. Anticancer genes are epigenetically regulated by insertional polymorphisms. The functional redundancy of BRG1 and BRM thwarts cancer development. Post‐translational modification of BRM and BRG1 alters the cellular roles of these proteins from growth inhibitors to growth promoters. The loss of cofactors (i.e. BRG1 and/or BRM) for RB‐mediated‐growth inhibition could preclude the function of CDK inhibitors used clinically. Specific SWI/SNF subunits are commonly mutated and inactivated in specific cancer types. Diminished SWI/SNF activity, but not the complete abrogation of function, is tumourigenic.

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The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential

Cited by 96 publications

References 38 publications

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

The SWI/SNF complex and cancer

SWI / SNF Chromatin Remodelling and Human Cancer

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