The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target

Navickas, Sophie M.; Giles, Katherine A.; Brettingham-Moore, Kate H.; Taberlay, Phillippa C.

doi:10.1038/s41388-023-02773-9

Cited by 15 publications

(8 citation statements)

References 109 publications

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“…Attempts to target SMARCA4 in various types of tumors, including non-smallcell lung cancer and brain tumors, have been reported in the preclinical phase [32,33]. SMARCA4 and SMARCA2 function as mutually exclusive catalytic subunits in the SWI/SNF complex.…”

Section: Discussionmentioning

confidence: 99%

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel

Yamashita,

Sewastjanow-Silva,

Yoshimura

et al. 2024

Cancers

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Background: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. Methods: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. Results: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. Conclusions: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

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Section: Discussionmentioning

confidence: 99%

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel

Yamashita,

Sewastjanow-Silva,

Yoshimura

et al. 2024

Cancers

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“…The activation of a subset of ISGs, while less straightforward to understand mechanistically, may be due to the loss of expression of an ISG transcriptional repressor. 42 The role of the SWI/SNF complex in promoting ISG transcription has been the focus of several earlier studies. 43 , 44 Moreover, PFI‐3 at higher concentrations than we used was found to decrease the expression of several genes.…”

Section: Discussionmentioning

confidence: 99%

Next‐generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma

Yang,

He,

Wang

et al. 2023

J Cellular Molecular Medi

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Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy‐resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI‐3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV‐129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV‐255 and IV‐275 had higher bioactivity than IV‐129, with IV‐255 selectively binding to the bromodomain of BRG1 and not BRM, while IV‐275 bound well to both BRG1 and BRM bromodomains. In contrast, IV‐191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV‐255 and IV‐275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next‐generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM.

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“…Also, biallelic mutations in the neuronspecific ACTL6B or haplosufficiency of ARID1B causes recessively inherited autism 24,85 , microduplication of ARID1A causes intellectual disability 92 , and SMARCC2 is a high-confidence autism gene [93][94][95][96][97] . As for brain tumors, SMARCA4 is recurrently mutated in multiple cancers 98 . Future studies are expected to reveal cause-effect association between these mutations, Pol2 elongation defects, and human maladies.…”

Section: Discussionmentioning

confidence: 99%

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Cornejo,

Venegas,

Sono

et al. 2023

Preprint

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Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.

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The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target

Cited by 15 publications

References 109 publications

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel

Next‐generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

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