TY - JOUR
T1 - Histone deacetylase inhibitor FK228 activates tumor suppressor Prdx1 with apoptosis induction in esophageal cancer cells
AU - Hoshino, Isamu
AU - Matsubara, Hisahiro
AU - Hanari, Naoyuki
AU - Mori, Mikito
AU - Nishimori, Takanori
AU - Yoneyama, Yasuo
AU - Akutsu, Yasunori
AU - Sakata, Haruhito
AU - Matsushita, Kazuyuki
AU - Seki, Naohiko
AU - Ochiai, Takenori
PY - 2005/11/1
Y1 - 2005/11/1
N2 - Purpose: The histone deacetylase inhibitor FK228 shows strong activity as a potent antitumor drug but its precise mechanism is still obscure. The purpose of this study is to reveal the effect of FK228 on gene expression in the cell and to determine the mechanism of the antitumor activity of FK228 for further clinical applications. Experimental Design and Results: Microarray analysis was applied to verify the gene expression profiles of 4,608 genes after FK228 treatment using human esophageal squamous cell cancer cell lines TTn and TE2. Among them, peroxiredoxin 1 (Prdx1), a member of the peroxiredoxin family of antioxidant enzymes having cell growth suppression activity, as well as p21 WAF1, were significantly activated by FK288. In addition, FK228 strongly inhibited the cell growth of TTn and TE2 by the induction of apoptosis. Further, chromatin immunoprecipitation analysis revealed that FK228 induced the accumulation of acetylated histones H3 and H4 in Prdx1 promoter, including the Sp1-binding site. In mouse xenograft models of TTn and TE2 cells, FK228 injection resulted in significant tumor regression as well as activated Prdx1 expression in tumor tissues. Prdx1 suppression by RNA interference hindered the antitumor effect of FK228. Conclusion: Our results indicate that the antitumor effect of FK228 in esophageal cancer cells is shown at least in part through Prdx1 activation by modulating acetylation of histones in the promoter, resulting in tumor growth inhibition with apoptosis induction.
AB - Purpose: The histone deacetylase inhibitor FK228 shows strong activity as a potent antitumor drug but its precise mechanism is still obscure. The purpose of this study is to reveal the effect of FK228 on gene expression in the cell and to determine the mechanism of the antitumor activity of FK228 for further clinical applications. Experimental Design and Results: Microarray analysis was applied to verify the gene expression profiles of 4,608 genes after FK228 treatment using human esophageal squamous cell cancer cell lines TTn and TE2. Among them, peroxiredoxin 1 (Prdx1), a member of the peroxiredoxin family of antioxidant enzymes having cell growth suppression activity, as well as p21 WAF1, were significantly activated by FK288. In addition, FK228 strongly inhibited the cell growth of TTn and TE2 by the induction of apoptosis. Further, chromatin immunoprecipitation analysis revealed that FK228 induced the accumulation of acetylated histones H3 and H4 in Prdx1 promoter, including the Sp1-binding site. In mouse xenograft models of TTn and TE2 cells, FK228 injection resulted in significant tumor regression as well as activated Prdx1 expression in tumor tissues. Prdx1 suppression by RNA interference hindered the antitumor effect of FK228. Conclusion: Our results indicate that the antitumor effect of FK228 in esophageal cancer cells is shown at least in part through Prdx1 activation by modulating acetylation of histones in the promoter, resulting in tumor growth inhibition with apoptosis induction.
UR - http://www.scopus.com/inward/record.url?scp=27744476753&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-05-0840
DO - 10.1158/1078-0432.CCR-05-0840
M3 - 記事
C2 - 16278420
AN - SCOPUS:27744476753
SN - 1078-0432
VL - 11
SP - 7945
EP - 7952
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -
