BRM: the core ATPase subunit of SWI/SNF chromatin-remodelling complex—a tumour suppressor or tumour-promoting factor?

Abstract

BRM (BRAHMA) is a core, SWI2/SNF2-type ATPase subunit of SWI/SNF chromatin-remodelling complex (CRC) involved in various important regulatory processes including development. Mutations in SMARCA2, a BRM-encoding gene as well as overexpression or epigenetic silencing were found in various human diseases including cancer. Missense mutations in SMARCA2 gene were recently connected with occurrence of Nicolaides–Baraitser genetics syndrome. By contrast, SMARCA2 duplication rather than mutations is characteristic for Coffin–Siris syndrome. It is believed that BRM usually acts as a tumour suppressor or a tumour susceptibility gene. However, other studies provided evidence that BRM function may differ depending on the cancer type and the disease stage, where BRM may play a role in the disease progression. The existence of alternative splicing forms of SMARCA2 gene, leading to appearance of truncated functional, loss of function or gain-of-function forms of BRM protein suggest a far more complicated mode of BRM-containing SWI/SNF CRCs actions. Therefore, the summary of recent knowledge regarding BRM alteration in various types of cancer and highlighting of differences and commonalities between BRM and BRG1, another SWI2/SNF2 type ATPase, will lead to better understanding of SWI/SNF CRCs function in cancer development/progression. BRM has been recently proposed as an attractive target for various anticancer therapies including the use of small molecule inhibitors, synthetic lethality induction or proteolysis-targeting chimera (PROTAC). However, such attempts have some limitations and may lead to severe side effects given the homology of BRM ATPase domain to other ATPases, as well as due to the tissue-specific appearance of BRM- and BRG1-containing SWI/SNF CRC classes. Thus, a better insight into BRM-containing SWI/SNF CRCs function in human tissues and cancers is clearly required to provide a solid basis for establishment of new safe anticancer therapies.

Copy number and transcriptome alterations associated with metastatic lesion response to treatment in colorectal cancer

“…50,51 The loss of chr 9p, the SMARCA2 gene location, was associated with aggressiveness in clear cell renal carcinoma and is used as a prognostic marker. 52,53 Validation of these candidates in an independent liver metastasis cohort remains to be investigated since Sveen et al did not include patients treated with bevacizumab. The loss of CDH1 being observed in a unique sample in the CAIRO2 cohort, association with patient outcome could not be confirmed in primary samples either.…”

SMARCA2 (BRM) expression is associated with enhanced survival in patients with breast cancer.

“…The SWI/SNF complex is recurrently mutated in a wide variety of human cancers, and genetic studies using mice have experimentally validated tumor suppressor functions for SWI/ SNF subunits including SMARCA4, also known as BAF (barrier to auto-integration factor) (4, 5, 6). SMARCA2 is the homolog of SMARCA4; SMARCA2 and SMARCA4 are mutually exclusive components of a SWI/SNF complex (1,6).…”

The Crosstalk Between Epigenetic Mechanisms and Alternative RNA Processing Regulation

“…During the last two decades, a growing number of studies have indicated that chromatin remodeling factors also play a role in alternative splicing. Brahma (BRM), the core adenosine triphosphatase (ATPase) subunit of the switch/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex, was firstly shown to facilitate the inclusion of alternative exons by interacting with Pol II to induce its stalling ( Figure 1A ; Batsché et al, 2006 ; Jancewicz et al, 2019 ). Actually, chromatin remodeler mediated-regulation of AS is an evolutionarily conserved mechanism across most species, such as in maize.…”

“…This study raised the intriguing possibility of cross talk between ncRNAs and AS/APA components. In addition, the diverse alternative mRNA processing-mediated protein variants thus generated immediately affect the properties of proteins, resulting in dysfunction of epigenetic regulators, including chromatin modification enzymes and remodeling factors ( Lei et al, 2014 ; Rusconi et al, 2017 ; Jancewicz et al, 2019 ).…”