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The SWI/SNF complex — chromatin and cancer

Key Points

  • The SWI/SNF complex is an evolutionarily conserved multi-subunit chromatin-remodelling complex, which uses the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin, and thereby regulate transcription of target genes.

  • This complex is implicated in cancer development, as several subunits either possess intrinsic tumour-suppressor activity or are required for the activity of other tumour-suppressor genes.

  • SNF5 (also known as INI1), a core subunit of SWI/SNF, is specifically inactivated in malignant rhabdoid tumours, a highly aggressive cancer of early childhood.

  • Whereas homozygous inactivation of Snf5 is embryonic lethal in mice, heterozygous mice are predisposed to develop cancers that readily metastasize and have loss of heterozygosity for Snf5. Inducible inactivation of conditional alleles of Snf5 results in extremely rapid and fully penetrant cancer development.

  • Specific mutations in BRG1 — an ATPase catalytic subunit of the SWI/SNF complex — have been identified in pancreatic, breast, lung and prostate cancer cell lines. Mice that are deficient in Brg1 are embryonic lethal, whereas haploinsufficient mice are predisposed to tumour development at a low incidence.

  • SWI/SNF complexes directly interact with tumour suppressors and oncogenes, such as RB, BRCA1, c-MYC and MLL (mixed-lineage leukaemia).

  • The SWI/SNF complex might also be involved in DNA synthesis, mitotic gene regulation and viral integration. The relationship between these activities and the role of the SWI/SNF complex in cancer development remains to be elucidated.

Abstract

The SWI/SNF complex is an evolutionarily conserved multi-subunit chromatin-remodelling complex, which uses the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin. Increasing evidence supports a role for this complex in cancer development, as several subunits possess intrinsic tumour-suppressor activity or are required for the activity of other tumour-suppressor genes. For example, conditional inactivation of the Snf5 gene resulted in a highly penetrant cancer phenotype in mice. So, what are the links between the SWI/SNF complex and cancer, and what mechanisms might facilitate its involvement in oncogenesis?

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Figure 1: Cooperation between two classes of chromatin-remodelling complexes.
Figure 2: Yeast and human SWI/SNF complexes and their subunits.
Figure 3: Mechanism of SWI/SNF nucleosome remodelling.
Figure 4: Distinct tumours result from inactivation of Snf5 and Brg1 in mice.
Figure 5: Method for generation of conditional Snf5 knockouts.
Figure 6: SWI/SNF is required for cell-cycle regulation by retinoblastoma.

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Acknowledgements

C.W.M.R. would like to acknowledge funding support from the Hope Street Kids foundation and the Claudia Adams Barr foundation.

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DATABASES

Cancer.gov

breast cancer

lung cancer

non-small-cell lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

LocusLink

BAF155

BAF170

BAF53

β-catenin

BRCA1

BRG1

BRM

CD44

CDK4

c-MYC

HOXA7

Ink4a

MLL

p53

RB

SNF5

WNT

Glossary

CHROMATIN-REMODELLING COMPLEX

A polypeptide complex that can compact or relax the secondary and tertiary structure of chromatin.

HOMOLOGUES

Genes (or proteins) that share a common ancestor and are usually similar in sequence.

ORTHOLOGUE

The form of a gene (or protein) in one species that corresponds most directly to a similar gene in another species.

KNUDSON'S TWO-HIT HYPOTHESIS

In 1971, Alfred Knudson proposed that two successive genetic 'hits' are required to turn a normal cell into a tumour cell and that, in familial cancers, one hit was inherited.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with a high frequency of LOH are believed to harbour tumour-suppressor genes.

PENETRANCE

The frequency with which individuals who carry a given gene will show the manifestations that are associated with the gene. If penetrance of a disease allele is 100%, then all individuals who carry that allele will express the associated disorder.

CRE RECOMBINASE

Bacteriophage-derived enzyme that causes DNA recombination between two LoxP recognition sites. A transgenic promoter can be used to direct Cre expression, thereby restricting inactivation of a gene to specific tissues or time points.

LOXP SITE

A LoxP (locus of X-ing over) site is a 34-base-pair (bp) directional DNA sequence that consists of two 13-bp inverted repeats separated by an 8-bp asymmetric spacer region.

KARYOTYPES

Complete set of chromosomes of a cell or organism.

HAPLOINSUFFICIENCY

A phenotypic state that results from loss of one functional allele of any given gene in diploid cells. Sometimes also called allelic insufficiency.

MENDELIAN FREQUENCY

Frequency of offspring with a particular phenotype or genotype expected in accordance with Mendel's Law.

DOMINANT-NEGATIVE MUTANT

A defective protein that inhibits wild-type function by retaining interaction capabilities that result in distortion or competition with normal proteins.

FANCONI ANAEMIA

A genetic disease that is characterized by progressive bone-marrow failure and cancer susceptibility.

HOMEOBOX

A 180-base-pair sequence that is present in many developmental genes. It encodes a DNA-binding helix–turn–helix motif, indicating that homeobox-containing gene products function as transcription factors.

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Roberts, C., Orkin, S. The SWI/SNF complex — chromatin and cancer. Nat Rev Cancer 4, 133–142 (2004). https://doi.org/10.1038/nrc1273

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