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Inhibition of Expression of the Chromatin Remodeling Gene, SNF2L, Selectively Leads to DNA Damage, Growth Inhibition, and Cancer Cell Death
SNF2L , a chromatin remodeling gene expressed in diverse tissues, cancers, and derived cell lines, contributes to the chromatin remodeling complex that facilitates transcription. Because of this wide expression, it has not been exploited as a cancer therapeutic target. However, based on our present...
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Published in: | Molecular cancer research 2009-12, Vol.7 (12), p.1984-1999 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | SNF2L , a chromatin remodeling gene expressed in diverse tissues, cancers, and derived cell lines, contributes to the chromatin
remodeling complex that facilitates transcription. Because of this wide expression, it has not been exploited as a cancer
therapeutic target. However, based on our present studies, we find that cancer cells, although expressing SNF2L at similar
levels as their normal counterparts, are sensitive to its knockdown. This is not observed when its imitation SWI ortholog,
SNF2H, is inhibited. SNF2L siRNA inhibition using two different siRNAs separately reduced SNF2L transcript levels and protein
in both normal and cancer lines, but only the cancer lines showed significant growth inhibition, DNA damage, a DNA damage
response, and phosphorylation of checkpoint proteins and marked apoptosis. DNA damage and the damage response preceded apoptosis
rather than being consequences of it. The damage response consisted of increased phosphorylation of multiple substrates including
ATR, BRCA1, CHK1, CHK2, and H2AX. Both the total and phosphorylated levels of p53 increased. The downstream targets of p53,
p21, GADD45A, and 14-3-3σ, were also upregulated. The alterations in checkpoint proteins included increased phosphorylated
cdc2 but not Rb, which resulted in a modest G 2 -M arrest. Although apoptosis may be mediated by Apaf-1/caspase 9, other caspases could be involved. Other members of the
chromatin remodeling or SWI/SNF gene families exhibited overall reduced levels of expression in the cancer lines compared
with the normal lines. This raised the hypothesis that cancers are sensitive to SNF2L knockdown because, unlike their normal
counterparts, they lack sufficient compensation from other family members. (Mol Cancer Res 2009;7(12):1984–99) |
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ISSN: | 1541-7786 1557-3125 |
DOI: | 10.1158/1541-7786.MCR-09-0119 |