Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity

Kothandapani, Anbarasi; Gopalakrishnan, Kathirvel; Kahali, Bhaskar; Reisman, David; Patrick, Steve M.

doi:10.1016/j.yexcr.2012.06.011

Cited by 56 publications

(49 citation statements)

References 46 publications

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“…It should be noted that some of these studies have reported functional differences, which is likely due to the comparison of cell lines derived from different tissue/tumor types that each have a unique genetic background. For example, BRG1 and BRM depletion had a much stronger effect on the survival of lung cancer cells [62] than what we observed for cervical cancer cells in this study.…”

Section: Discussioncontrasting

confidence: 51%

SWI/SNF complexes are required for full activation of the DNA-damage response

et al. 2015

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SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated in ~20% of all human primary tumors. Yet our knowledge of their tumor-suppressor mechanism is limited. To investigate the role of SWI/SNF complexes in the DNA-damage response (DDR), we used shRNAs to deplete BRG1 and BRM and then exposed these cells to a panel of 6 genotoxic agents. Compared to controls, the shRNA knockdown cells were hypersensitive to certain genotoxic agents that cause double-strand breaks (DSBs) associated with stalled/collapsed replication forks but not to ionizing radiation-induced DSBs that arise independently of DNA replication. These findings were supported by our analysis of DDR kinases, which demonstrated a more prominent role for SWI/SNF in the activation of the ATR-Chk1 pathway than the ATM-Chk2 pathway. Surprisingly, γH2AX induction was attenuated in shRNA knockdown cells exposed to a topoisomerase II inhibitor (etoposide) but not to other genotoxic agents including IR. However, this finding is compatible with recent studies linking SWI/SNF with TOP2A and TOP2BP1. Depletion of BRG1 and BRM did not result in genomic instability in a tumor-derived cell line but did result in nucleoplasmic bridges in normal human fibroblasts. Taken together, these results suggest that SWI/SNF tumor-suppressor activity involves a role in the DDR to attenuate replicative stress and genomic instability. These results may also help to inform the selection of chemotherapeutics for tumors deficient for SWI/SNF function.

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Section: Discussioncontrasting

confidence: 51%

SWI/SNF complexes are required for full activation of the DNA-damage response

et al. 2015

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“…In addition, SWI/SNF in general has been shown to play roles in cellular differentiation and organ development 45–49 . Interestingly, the SWI/SNF complex may also increase sensitivity to cisplatin 50 but increase resistance to EGFR inhibitors. Indeed, there is no shortage of feasible mechanisms by which BRM loss could impact cancer development and clinical outcomes.…”

Section: Discussionmentioning

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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“…Most of the genes constituting this panel serve as biomarkers for efficacy, prognosis, diagnosis, disease progression (targeting inflammation, oxidative stress and vesiculation gene networks) and response to therapy [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. Vitamin D mediated genetic networks such as those identified in our study, for example inflammation, oxidative stress and membrane vesicle biogenesis pathways in 143B cells, shed insight into the mechanism(s) underlying antineoplastic effects of vitamin D in human OS.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells

Garimella

Tadikonda

Tawfik

et al. 2017

IJMS

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Osteosarcoma (OS) is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human OS. Vitamin D treatment of 143B OS cells induced significant and novel changes in the expression of genes that regulate: (a) inflammation and immunity; (b) formation of reactive oxygen species, metabolism of cyclic nucleotides, sterols, vitamins and mineral (calcium), quantity of gap junctions and skeletogenesis; (c) bone mineral density; and (d) cell viability of skeletal cells, aggregation of bone cancer cells and exocytosis of secretory vesicles. Ingenuity pathway analysis revealed significant reduction in Runx2 target genes such as fibroblast growth factor -1, -12 (FGF1 and FGF12), bone morphogenetic factor-1 (BMP1), SWI/SNF related, matrix associated actin dependent regulator of chromatin subfamily a, member 4 (SMARCA4), Matrix extracellular phosphoglycoprotein (MEPE), Integrin, β4 (ITGBP4), Matrix Metalloproteinase -1, -28 (MMP1 and MMP28), and signal transducer and activator of transcription-4 (STAT4) in vitamin D treated 143B OS cells. These genes interact with the inflammation, oxidative stress and membrane vesicle biogenesis gene networks. Vitamin D not only inhibited the expression of Runx2 target genes MMP1, MMP28 and kallikrein related peptidase-7 (KLK7), but also migration and invasion of 143B OS cells. Vitamin D regulated Runx2 target genes or their products represent potential therapeutic targets and laboratory biomarkers for applications in translational oncology.

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Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity

Cited by 56 publications

References 46 publications

SWI/SNF complexes are required for full activation of the DNA-damage response

SWI/SNF complexes are required for full activation of the DNA-damage response

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

Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells

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