TY - JOUR
T1 - Promoter characterization of Semaphorin SEMA3F, a tumor suppressor gene
AU - Kusy, Sophie
AU - Potiron, Vincent
AU - Zeng, Chan
AU - Franklin, Wilbur
AU - Brambilla, Elisabeth
AU - Minna, John
AU - Drabkin, Harry A.
AU - Roche, Joëlle
N1 - Funding Information:
This work was supported by ARC (Association pour la Recherche sur le Cancer) et Ligue Nationale Contre le Cancer, Comités de la Vienne et de la Charente for SK and JR, grants CA58187 and CA85070 from the U.S. National Cancer Institute for HD and grants NCI P50 CA70907 and NCI CA71618 for JDM.
PY - 2005/7/25
Y1 - 2005/7/25
N2 - The tumor suppressor gene, Semaphorin SEMA3F, is frequently downregulated in lung cancer. Understanding the specific mechanism of SEMA3F suppression should be informative in terms of epithelial carcinogenesis and potential therapeutic interventions. Although a CpG-island is located 5083-3927 nt upstream of the translation start site, there have been no previous reports dealing with SEMA3F promoter regulation. We have now mapped the transcriptional initiation sites within the CpG-island and defined the region necessary for transcriptional activation. We then looked for evidence of SEMA3F promoter methylation since SEMA3F mutations are rare. By Southern blot and methylation-specific PCR assays, we identified a region in cell lines (i.e., area d at position minus 3850-3644 nt) for which methylation was significantly (P < 0.0001) correlated with loss of expression. However, histone deacetylase inhibition with Trichostatin A was much more effective than 5-aza-2′-deoxycytidine in stimulating SEMA3F. Our results suggest that while SEMA3F promoter methylation correlates with repression, chromatin remodeling through histone deacetylase inhibition is sufficient to activate SEMA3F expression.
AB - The tumor suppressor gene, Semaphorin SEMA3F, is frequently downregulated in lung cancer. Understanding the specific mechanism of SEMA3F suppression should be informative in terms of epithelial carcinogenesis and potential therapeutic interventions. Although a CpG-island is located 5083-3927 nt upstream of the translation start site, there have been no previous reports dealing with SEMA3F promoter regulation. We have now mapped the transcriptional initiation sites within the CpG-island and defined the region necessary for transcriptional activation. We then looked for evidence of SEMA3F promoter methylation since SEMA3F mutations are rare. By Southern blot and methylation-specific PCR assays, we identified a region in cell lines (i.e., area d at position minus 3850-3644 nt) for which methylation was significantly (P < 0.0001) correlated with loss of expression. However, histone deacetylase inhibition with Trichostatin A was much more effective than 5-aza-2′-deoxycytidine in stimulating SEMA3F. Our results suggest that while SEMA3F promoter methylation correlates with repression, chromatin remodeling through histone deacetylase inhibition is sufficient to activate SEMA3F expression.
KW - Epigenetic modifications
KW - Lung cancer
KW - Reporter gene
KW - Semaphorin SEMA3F promoter
KW - Transcriptional initiation site
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U2 - 10.1016/j.bbaexp.2005.05.008
DO - 10.1016/j.bbaexp.2005.05.008
M3 - Article
C2 - 16005989
AN - SCOPUS:22444446949
SN - 0167-4781
VL - 1730
SP - 66
EP - 76
JO - Biochimica et Biophysica Acta - Gene Structure and Expression
JF - Biochimica et Biophysica Acta - Gene Structure and Expression
IS - 1
ER -