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Review
. 2022 Jul 27;14(15):3645.
doi: 10.3390/cancers14153645.

SMARCB1-Deficient Cancers: Novel Molecular Insights and Therapeutic Vulnerabilities

Garrett W Cooper  1   2 , Andrew L Hong  1   2   3
Affiliations
Review

SMARCB1-Deficient Cancers: Novel Molecular Insights and Therapeutic Vulnerabilities

Garrett W Cooper et al. Cancers (Basel). .

Abstract

SMARCB1 is a critical component of the BAF complex that is responsible for global chromatin remodeling. Loss of SMARCB1 has been implicated in the initiation of cancers such as malignant rhabdoid tumor (MRT), atypical teratoid rhabdoid tumor (ATRT), and, more recently, renal medullary carcinoma (RMC). These SMARCB1-deficient tumors have remarkably stable genomes, offering unique insights into the epigenetic mechanisms in cancer biology. Given the lack of druggable targets and the high mortality associated with SMARCB1-deficient tumors, a significant research effort has been directed toward understanding the mechanisms of tumor transformation and proliferation. Accumulating evidence suggests that tumorigenicity arises from aberrant enhancer and promoter regulation followed by dysfunctional transcriptional control. In this review, we outline key mechanisms by which loss of SMARCB1 may lead to tumor formation and cover how these mechanisms have been used for the design of targeted therapy.

Keywords: SMARCB1-deficient cancer; chromatin; epigenetics; rhabdoid tumor; structure; therapeutics.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Cancer-associated mutations and molecular interactions of SMARCB1. Data obtained from COSMIC (v95) reveal a clustering of mutations in the C-terminal coiled-coiled domain as well as a high preponderance of truncation mutations on the N-terminal end. (a) Frequency of cancer associated mutations in SMARCB1. Nonsense mutations and frameshift mutations are denoted by (*). The four known functional domains of SMARCB1 and their reported molecular interactions are shown. (b) The proportion of each mutation type within the COSMIC dataset. In-frame and frameshift mutations include both deletions and insertions.
Figure 2
Figure 2
Conservation of SMARCB1 across seven eukaryotic species: H. sapiens-NP_003064.2, M. musculus-BAB12427.1, D. rerio-NP_001007297.1, C. elegans-NP_001369845.1, S. cerevisiae-ONH79494.1, and A. thaliana-NP_001189918. Light green boxes represent amino acid residues that match the H. sapiens SMARCB1 sequence. Dark green residues represent amino acid residues that are conserved in all seven eukaryotic species used in this analysis.
Figure 3
Figure 3
Role of SMARCB1 within the BAF complex in regulating gene expression.
Figure 4
Figure 4
Therapeutic vulnerabilities discovered in SMARCB1-deficient cancers.
See this image and copyright information in PMC

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References

    1. Laurent B.C., Treitel M.A., Carlson M. The SNF5 protein of Saccharomyces cerevisiae is a glutamine- and proline-rich transcriptional activator that affects expression of a broad spectrum of genes. Mol. Cell Biol. 1990;10:5616–5625. doi: 10.1128/mcb.10.11.5616-5625.1990. - DOI - PMC - PubMed
    1. Neigeborn L., Carlson M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics. 1984;108:845–858. doi: 10.1093/genetics/108.4.845. - DOI - PMC - PubMed
    1. Kalpana G.V., Marmon S., Wang W., Crabtree G.R., Goff S.P. Binding and Stimulation of HIV-1 Integrase by a Human Homolog of Yeast Transcription Factor SNF5. Science. 1994;266:2002–2006. doi: 10.1126/science.7801128. - DOI - PubMed
    1. Versteege I., Sévenet N., Lange J., Rousseau-Merck M.F., Ambros P., Handgretinger R., Aurias A., Delattre O. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394:203–206. doi: 10.1038/28212. - DOI - PubMed
    1. Margol A.S., Judkins A.R. Pathology and diagnosis of SMARCB1-deficient tumors. Cancer Genet. 2014;207:358–364. doi: 10.1016/j.cancergen.2014.07.004. - DOI - PubMed

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