TY - JOUR
T1 - Singular v Dual inhibition of SNF2L and its isoform, SNF2LT, have
T2 - Similar effects on DNA Damage but opposite effects on the DNA: Damage response, cancer cell growth arrest and apoptosis
AU - Ye, Yin
AU - Xiao, Yi
AU - Wang, Wenting
AU - Gao, Jian Xin
AU - Yearsley, Kurtis
AU - Yan, Quintao
AU - Barsky, Sanford H.
PY - 2012/4
Y1 - 2012/4
N2 - SNF2L, an ATPase chromatin remodeling gene nearly ubiquitously expressed in diverse tissues, cancers, and derived cell lines, contributes to the chromatin remodeling complex that facilitates transcription. Because of this near ubiquitous expression, it has not been exploited as a cancer therapeutic target. However, in a recent study, we found that highly malignant cancer cells, although expressing SNF2L at similar levels as their normal counterparts, were sensitive to its knockdown. Only the highly malignant (HM) lines showed significant growth inhibition, DNA damage, a DNA damage response, and phosphorylation of checkpoint proteins and marked apoptosis. In studying SNF2L, we discovered a novel truncated isoform, SNF2LT which, when compared to full length SNF2L, lacked three important domains: HAND, SANT and SLIDE. Although truncated isoforms usually have antagonistic functions to their parental molecule, here SNF2LT knockdown had similar effects to the knockdown of its parental molecule, SNF2L, of inducing DNA damage, a DNA damage response, cell cycle arrest and apoptosis selectively in cancer cell lines. However dual SNF2L and SNF2LT knockdown, while inducing DNA damage, did not result in a DNA damage response, a cell cycle arrest and apoptosis. In fact HM lines subjected to dual knockdown paradoxically exhibited sustained cell growth. Our findings indicate that the ratio of SNF2L to its isoform tightly regulates the cancer cell's response to DNA damage. Cancer cell lines which endogenously express low levels of both SNF2L and its isoform mimic the situation of dual knockdown and permit DNA damage which is allowed to propagate unchecked.
AB - SNF2L, an ATPase chromatin remodeling gene nearly ubiquitously expressed in diverse tissues, cancers, and derived cell lines, contributes to the chromatin remodeling complex that facilitates transcription. Because of this near ubiquitous expression, it has not been exploited as a cancer therapeutic target. However, in a recent study, we found that highly malignant cancer cells, although expressing SNF2L at similar levels as their normal counterparts, were sensitive to its knockdown. Only the highly malignant (HM) lines showed significant growth inhibition, DNA damage, a DNA damage response, and phosphorylation of checkpoint proteins and marked apoptosis. In studying SNF2L, we discovered a novel truncated isoform, SNF2LT which, when compared to full length SNF2L, lacked three important domains: HAND, SANT and SLIDE. Although truncated isoforms usually have antagonistic functions to their parental molecule, here SNF2LT knockdown had similar effects to the knockdown of its parental molecule, SNF2L, of inducing DNA damage, a DNA damage response, cell cycle arrest and apoptosis selectively in cancer cell lines. However dual SNF2L and SNF2LT knockdown, while inducing DNA damage, did not result in a DNA damage response, a cell cycle arrest and apoptosis. In fact HM lines subjected to dual knockdown paradoxically exhibited sustained cell growth. Our findings indicate that the ratio of SNF2L to its isoform tightly regulates the cancer cell's response to DNA damage. Cancer cell lines which endogenously express low levels of both SNF2L and its isoform mimic the situation of dual knockdown and permit DNA damage which is allowed to propagate unchecked.
KW - DNA damage
KW - NURF
KW - SNF2l
KW - SNF2lt
UR - http://www.scopus.com/inward/record.url?scp=84867181739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867181739&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.479
DO - 10.18632/oncotarget.479
M3 - Article
C2 - 22577152
AN - SCOPUS:84867181739
SN - 1949-2553
VL - 3
SP - 475
EP - 489
JO - Oncotarget
JF - Oncotarget
IS - 4
ER -