The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

Wu, Qiong; Madany, Pasil; Dobson, Jason R.; Schnabl, Jake; Sharma, Soni; Smith, Tara C.; Wijnen, André J. van; Stein, Janet L.; Lian, Jane B.; Muthuswami, Rohini; Imbalzano, Anthony N.; Nickerson, Jeffrey A.

doi:10.18632/oncotarget.9505

Cited by 55 publications

(66 citation statements)

References 71 publications

(89 reference statements)

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“…Chromatin remodeling complexes have not been viewed as a drugable target until recently, but our work shows that the BRG1 chromatin remodeling enzyme is an especially promising target for epigenetic breast cancer chemotherapy (28, 59, 85). Inhibition of BRG1 function decreases tumor cell proliferation, decreases tumor mass in mouse models, and potentiates tumor cell killing by clinically used chemotherapy drugs.…”

Section: Targeting Brg1 For Breast Cancer Therapymentioning

confidence: 92%

“…By these mechanisms, mTORC1 increases the transcription of lipogenic genes, including key enzymes in fatty acid synthesis, such as acetyl CoA carboxylase (ACC), ATP citrate lyase (ACLY), and fatty acid synthase (FASN). As we shall discuss, we have shown Lipin1 and each of these enzymes involved in fatty acid synthesis to be transcriptionally regulated by Brahma-related gene 1 (BRG1), a chromatin remodeling enzyme (28). …”

Section: Transcriptional Regulation Of Metabolismmentioning

confidence: 99%

“…We discovered that BRG1 promotes breast cancer by reprogramming lipid synthesis (28) as shown in Figure 1. BRG1 knockdown reduced the rate of chloroform/methanol extractable lipid synthesis by 35% while glucose uptake remained unchanged.…”

Section: Brg1 Is Necessary For Fatty Acid Biosynthesis In Support Of mentioning

confidence: 99%

“…Knockdown or inhibition of BRG1 decreases levels of all three enzymes with resulting decreases in lipid synthesis and decreases in breast tumor cell proliferation. Proliferation can be rescued with palmitate supplementation (28). Acetyl CoA is also the source of acetyl groups for histone acetylation which generally upregulates transcription and may cooperate with BRG1 in the regulation of gene expression.…”

Section: Brg1 Is Necessary For Fatty Acid Biosynthesis In Support Of mentioning

confidence: 99%

“…ADAADi decreases lipid biosynthesis in breast cancer cells (28) and also sensitizes cells to chemotherapy drugs, just as BRG1 knockdown does (85). After pretreatment with ADAADi, cells were exposed to different doses of six clinically used chemotherapy drugs and cell viability was assayed by MTT.…”

Section: Targeting Brg1 For Breast Cancer Therapymentioning

confidence: 99%

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Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming

Nickerson

2017

Front. Oncol.

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Tumor cells reprogram their metabolism to survive and grow in a challenging microenvironment. Some of this reprogramming is performed by epigenetic mechanisms. Epigenetics is in turn affected by metabolism; chromatin modifying enzymes are dependent on substrates that are also key metabolic intermediates. We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation. The mechanism for this requirement is the BRG1-dependent transcription of key lipogenic enzymes and regulators. Reduction in lipid synthesis lowers proliferation rates, which can be restored by palmitate supplementation. This work has established BRG1 as an attractive target for breast cancer therapy. Unlike genetic alterations, epigenetic mechanisms are reversible, promising gentler therapies without permanent off-target effects at distant sites.

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Section: Targeting Brg1 For Breast Cancer Therapymentioning

confidence: 92%

Section: Transcriptional Regulation Of Metabolismmentioning

confidence: 99%

Section: Brg1 Is Necessary For Fatty Acid Biosynthesis In Support Of mentioning

confidence: 99%

Section: Brg1 Is Necessary For Fatty Acid Biosynthesis In Support Of mentioning

confidence: 99%

Section: Targeting Brg1 For Breast Cancer Therapymentioning

confidence: 99%

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Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming

Nickerson

2017

Front. Oncol.

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Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Jia

et al. 2022

Cancer Communications

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Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post‐transcriptional levels. Epigenetic modifiers, chromatin remodelers and non‐coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic‐metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

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SWI/SNF chromatin remodeling complex and glucose metabolism are deregulated in advanced bladder cancer

et al. 2020

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Bladder cancer (BC) is a frequently diagnosed malignancy affecting predominantly adult and elderly populations. It is expected that due to the longer life time, BC will become even more frequent in the future; thus in consequence, it will represent serious health problem of older society part. The treatment of advanced BC is mostly ineffective due to its very aggressive behavior. So far, no effective targeted therapy is used for BC treatment. Here, we found that BC is characterized by lower protein levels of BRM, INI1, and BAF155 main subunits of SWI/SNF chromatin remodeling complex (CRC) which is involved in global control of gene expression and influences various important cellular processes like: cell cycle control, apoptosis, DNA repair, etc. Moreover, the expression of SMARCA2, a BRM encoding gene, strongly correlated with BC metastasis and expression of such metabolic genes as PKM2 and PRKAA1. Furthermore, the analysis of T24 and 5637 commonly used BC cell lines revealed different expression levels of metabolic genes including FBP1 gene encoding Frutose-1,6-Bisphosphatase, an enzyme controlling glycolysis flux and gluconeogenesis. The tested BC cell lines exhibited various molecular and metabolic alterations as well as differential glucose uptake, growth rate, and migration potential. We have shown that BRM subunit is involved in the transcriptional control of genes encoding metabolic enzymes.Moreover, we found that the FBP1 expression level and the SWI/SNF CRCs may serve as markers of molecular subtypes of BC. Collectively, this study may provide a new knowledge about the molecular and metabolic BC subtypes which likely will be of high importance for the clinic in the future.

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The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

Cited by 55 publications

References 71 publications

Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming

Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

SWI/SNF chromatin remodeling complex and glucose metabolism are deregulated in advanced bladder cancer

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