Flavonoids from each of the six structural groups reactivate BRM, a possible cofactor for the anticancer effects of flavonoids

Kahali, Bhaskar; Marquez, Stefanie B.; Thompson, Kenneth W.; Yu, Jie; Gramling, Sarah; Lü, Li; Aponick, Aaron; Reisman, David

doi:10.1093/carcin/bgu117

Cited by 20 publications

(19 citation statements)

References 68 publications

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“…Unlike adenomas, which were observed to be well tolerated even when they numbered as high as ∼30-50 per mouse [20], the development of these malignant lung adenocarcinomas eventually caused visible distress: weight loss >10%, lack of movement, disheveled appearance, and tachypnea. The majority of observed tumors were harvested when one or more of these physical changes were observed as required by IACUC.…”

Section: Resultsmentioning

confidence: 99%

Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

et al. 2016

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Inactivation of Brg1 and Brm accelerated lung tumor development, shortened tumor latency, and caused a loss of differentiation. Tumors with Brg1 and/or Brm loss recapitulated the evolution of human lung cancer as observed by the development of local tumor invasion as well as distal tumor metastasis, thereby making this model useful in lung cancer studies. Brg1 loss contributed to metastasis in part by driving E-cadherin loss and Vimentin up-regulation. By changing more than 6% of the murine genome with the down-regulation of tumor suppressors, DNA repair, differentiation and cell adhesion genes, and the concomitant up-regulation of oncogenes, angiogenesis, metastasis and antiapoptosis genes, caused by the dual loss of Brg1/Brm further accelerated tumor development. Additionally, this Brg1/Brm-driven change in gene expression resulted in a nearly two-fold increase in tumorigenicity in Brg1/Brm knockout mice compared with wild type mice. Most importantly, Brg1/Brm-driven lung cancer development histologically and clinically reflects human lung cancer development thereby making this GEMM model potentially useful.

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Section: Resultsmentioning

confidence: 99%

Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

et al. 2016

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“…Our western blot method has been described elsewhere [34, 35]. Briefly, the cells were harvested, and total protein was extracted using a urea-based lysis buffer, as described previously.…”

Section: Methodsmentioning

confidence: 99%

BRG1 and BRM loss selectively impacts RB and P53, respectively: BRG1 and BRM have differential functions in vivo

et al. 2016

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The SWI/SNF complex is an important regulator of gene expression that functions by interacting with a diverse array of cellular proteins. The catalytic subunits of SWI/SNF, BRG1 and BRM, are frequently lost alone or concomitantly in a range of different cancer types. This loss abrogates SWI/SNF complex function as well as the functions of proteins that are required for SWI/SNF function, such as RB1 and TP53. Yet while both proteins are known to be dependent on SWI/SNF, we found that BRG1, but not BRM, is functionally linked to RB1, such that loss of BRG1 can directly or indirectly inactivate the RB1 pathway. This newly discovered dependence of RB1 on BRG1 is important because it explains why BRG1 loss can blunt the growth-inhibitory effect of tyrosine kinase inhibitors (TKIs). We also observed that selection for Trp53 mutations occurred in Brm-positive tumors but did not occur in Brm-negative tumors. Hence, these data indicate that, during cancer development, Trp53 is functionally dependent on Brm but not Brg1. Our findings show for the first time the key differences in Brm- and Brg1-specific SWI/SNF complexes and help explain why concomitant loss of Brg1 and Brm frequently occurs in cancer, as well as how their loss impacts cancer development.

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“…Potential prognostic implications are important, as involvement of the BRM pathway in tumors may identify a subset of individuals with worse outcome that potentially could benefit from focused development of a class of drugs targeting BRM re-expression. That the BRM polymorphisms are associated with epigenetic factors is unique, but even more so when such epigenetic silencing has been reversed by a variety of compounds and drugs such as certain non-steroidal anti-inflammatory drugs (indoprofen), and flavonoids (genistein) 30,31 .…”

Section: Introductionmentioning

confidence: 99%

BRM Promoter Polymorphisms and Survival of Advanced Non–Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial

Liu

Cuffe

Liang

et al. 2017

Clinical Cancer Research

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Introduction BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741, BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. Methods Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed. Results Carrying the homozygous variants of both polymorphisms (“double homozygotes”, DH) when compared with those carrying the double wild-type, was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95%CI: 1.9–4.0). This was confirmed in the BR.24 trial (aHR 8.97, 95%CI: 3.3–18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (p<0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH. Conclusion Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival.

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Flavonoids from each of the six structural groups reactivate BRM, a possible cofactor for the anticancer effects of flavonoids

Cited by 20 publications

References 68 publications

Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

BRG1 and BRM loss selectively impacts RB and P53, respectively: BRG1 and BRM have differential functions in vivo

BRM Promoter Polymorphisms and Survival of Advanced Non–Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial

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