Histone deacetylase inhibitor FK228 activates tumor suppressor Prdx1 with apoptosis induction in esophageal cancer cells.
OBJECTIVE
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.


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 T.Tn 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 T.Tn 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 T.Tn 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.


CONCLUSIONS
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.
Hoshino
Isamu
I
Department of Frontier Surgery (M9), Graduate School of Medicine, Chiba University, Japan.
Matsubara
Hisahiro
H
Hanari
Naoyuki
N
Mori
Mikito
M
Nishimori
Takanori
T
Yoneyama
Yasuo
Y
Akutsu
Yasunori
Y
Sakata
Haruhito
H
Matsushita
Kazuyuki
K
Seki
Naohiko
N
Ochiai
Takenori
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004947:Esophagus / Q000473:pathology; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000737:chemistry; D006801:Humans; D020287:In Situ Nick-End Labeling; D007438:Introns; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010544:Peroxidases / Q000378:metabolism*; D054464:Peroxiredoxins; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D047630:Depsipeptides; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012313:RNA; C087123:romidepsin; D010544:Peroxidases; C515940:PRDX1 protein, human; D054464:Peroxiredoxins