A Histone deacetylase inhibitor suppresses epithelial-mesenchymal transition and attenuates chemoresistance in biliary tract cancer

Takuya Sakamoto, Shogo Kobayashi, Daisaku Yamada, Hiroaki Nagano, Akira Tomokuni, Yoshito Tomimaru, Takehiro Noda, Kunihito Gotoh, Tadafumi Asaoka, Hiroshi Wada, Koichi Kawamoto, Shigeru Marubashi, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine- resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.

Original languageEnglish
Article numbere0145985
JournalPLoS One
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 4 2016
Externally publishedYes

Fingerprint

Biliary Tract Neoplasms
biliary tract
transforming growth factor beta 1
histone deacetylase
Histone Deacetylase Inhibitors
Epithelial-Mesenchymal Transition
gemcitabine
Transforming Growth Factor beta
neoplasms
cell lines
Cells
Cell Line
vimentin
mice
vorinostat
bromides
epigenetics
metastasis
Inbred NOD Mouse
Vimentin

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

A Histone deacetylase inhibitor suppresses epithelial-mesenchymal transition and attenuates chemoresistance in biliary tract cancer. / Sakamoto, Takuya; Kobayashi, Shogo; Yamada, Daisaku; Nagano, Hiroaki; Tomokuni, Akira; Tomimaru, Yoshito; Noda, Takehiro; Gotoh, Kunihito; Asaoka, Tadafumi; Wada, Hiroshi; Kawamoto, Koichi; Marubashi, Shigeru; Eguchi, Hidetoshi; Doki, Yuichiro; Mori, Masaki.

In: PLoS One, Vol. 11, No. 1, e0145985, 04.01.2016.

Research output: Contribution to journalArticle

Sakamoto, T, Kobayashi, S, Yamada, D, Nagano, H, Tomokuni, A, Tomimaru, Y, Noda, T, Gotoh, K, Asaoka, T, Wada, H, Kawamoto, K, Marubashi, S, Eguchi, H, Doki, Y & Mori, M 2016, 'A Histone deacetylase inhibitor suppresses epithelial-mesenchymal transition and attenuates chemoresistance in biliary tract cancer', PLoS One, vol. 11, no. 1, e0145985. https://doi.org/10.1371/journal.pone.0145985
Sakamoto, Takuya ; Kobayashi, Shogo ; Yamada, Daisaku ; Nagano, Hiroaki ; Tomokuni, Akira ; Tomimaru, Yoshito ; Noda, Takehiro ; Gotoh, Kunihito ; Asaoka, Tadafumi ; Wada, Hiroshi ; Kawamoto, Koichi ; Marubashi, Shigeru ; Eguchi, Hidetoshi ; Doki, Yuichiro ; Mori, Masaki. / A Histone deacetylase inhibitor suppresses epithelial-mesenchymal transition and attenuates chemoresistance in biliary tract cancer. In: PLoS One. 2016 ; Vol. 11, No. 1.
@article{ae0022292fa24acfa7c5a2448850f3ae,
title = "A Histone deacetylase inhibitor suppresses epithelial-mesenchymal transition and attenuates chemoresistance in biliary tract cancer",
abstract = "Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine- resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.",
author = "Takuya Sakamoto and Shogo Kobayashi and Daisaku Yamada and Hiroaki Nagano and Akira Tomokuni and Yoshito Tomimaru and Takehiro Noda and Kunihito Gotoh and Tadafumi Asaoka and Hiroshi Wada and Koichi Kawamoto and Shigeru Marubashi and Hidetoshi Eguchi and Yuichiro Doki and Masaki Mori",
year = "2016",
month = "1",
day = "4",
doi = "10.1371/journal.pone.0145985",
language = "English",
volume = "11",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",

}

TY - JOUR

T1 - A Histone deacetylase inhibitor suppresses epithelial-mesenchymal transition and attenuates chemoresistance in biliary tract cancer

AU - Sakamoto, Takuya

AU - Kobayashi, Shogo

AU - Yamada, Daisaku

AU - Nagano, Hiroaki

AU - Tomokuni, Akira

AU - Tomimaru, Yoshito

AU - Noda, Takehiro

AU - Gotoh, Kunihito

AU - Asaoka, Tadafumi

AU - Wada, Hiroshi

AU - Kawamoto, Koichi

AU - Marubashi, Shigeru

AU - Eguchi, Hidetoshi

AU - Doki, Yuichiro

AU - Mori, Masaki

PY - 2016/1/4

Y1 - 2016/1/4

N2 - Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine- resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.

AB - Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine- resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.

UR - http://www.scopus.com/inward/record.url?scp=84954053900&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84954053900&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0145985

DO - 10.1371/journal.pone.0145985

M3 - Article

VL - 11

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 1

M1 - e0145985

ER -