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Review
. 2019 Nov 13;12(1):68.
doi: 10.1186/s13072-019-0315-4.

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

Iga Jancewicz  1 , Janusz A Siedlecki  1 , Tomasz J Sarnowski  2 , Elzbieta Sarnowska  3
Affiliations
Review

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

Iga Jancewicz et al. Epigenetics Chromatin. .

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.

Keywords: BRM; Cancer; Epigenetics; SMARCA2; SWI/SNF chromatin-remodelling complex (CRC); Small molecule inhibitors; Synthetic lethality.

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Conflict of interest statement

The authors declare no competing of interests.

Figures

Fig. 1
Fig. 1
The phenotypic differences and commonalities between NCBRS and CSS. The red lines correspond to mutation sites in SMARCA2 and SMARCA4 genes according to [136]
Fig. 2
Fig. 2
BRM-involving cellular processes. BRM protein is involved in a variety of cellular processes both in healthy/normal and cancerous cells; for example, gene expression control, alternative splicing, cell cycle control, participating in hormonal response and miRNA transcription and signalling. In pathological situations, in cancer cells, BRM can leave the cell nuclei and migrate to cytoplasm or cell membrane, although specific effects of BRM in these locations are unknown
Fig. 3
Fig. 3
Schematic summary of BRM role in cancer development. ↑—upregulation; ↓—downregulation; TNBC triple-negative breast cancer, HCC hepatocellular carcinoma, UATC upper aerodigestive tract, SCCOHT small cell carcinoma of the ovary, hypercalcaemic type, OCCC ovarian clear cell carcinoma; OCC ovarian cell carcinoma, HNSCC head and neck squamous cell carcinoma, ACC adenoid cystic carcinoma; NSCLC non-small cell lung cancer; AD adenocarcinoma od the lung, LC large cell carcinoma of the lung; PL pleomorphic carcinoma of the lung; ccRCC clear cell renal cell carcinoma, NMSC non-melanoma skin cancer
Fig. 4
Fig. 4
Cancer treatment related to BRM protein. Ideas for utilising BRM in anticancer therapy are emerging. Such therapies, taken currently into consideration, are based on BRM level restoration by, e.g. HDAC inhibitors and E2F inhibitors. A very promising but demanding idea is based on a synthetic lethality approach, targeted against BRM ATPase domain or bromodomain
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