Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer

Sofie Claerhout, Jae Yun Lim, Woonyoung Choi, Yun Yong Park, KyoungHyun Kim, Sang Bae Kim, Ju Seog Lee, Gordon Mills, Jae Yong Cho

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Background: Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

Original languageEnglish (US)
Article numbere24662
JournalPLoS One
Volume6
Issue number9
DOIs
StatePublished - Sep 9 2011
Externally publishedYes

Fingerprint

stomach neoplasms
Transcriptome
Gene expression
Stomach Neoplasms
gene expression
therapeutics
Autophagy
autophagy
Gastrointestinal Agents
Therapeutics
Genes
Cells
Tissue
Lead compounds
vorinostat
Histone Deacetylase Inhibitors
cell lines
Gene Expression
Cell Line
Neoplasms

ASJC Scopus subject areas

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

Cite this

Claerhout, S., Lim, J. Y., Choi, W., Park, Y. Y., Kim, K., Kim, S. B., ... Cho, J. Y. (2011). Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. PLoS One, 6(9), [e24662]. https://doi.org/10.1371/journal.pone.0024662

Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. / Claerhout, Sofie; Lim, Jae Yun; Choi, Woonyoung; Park, Yun Yong; Kim, KyoungHyun; Kim, Sang Bae; Lee, Ju Seog; Mills, Gordon; Cho, Jae Yong.

In: PLoS One, Vol. 6, No. 9, e24662, 09.09.2011.

Research output: Contribution to journalArticle

Claerhout, S, Lim, JY, Choi, W, Park, YY, Kim, K, Kim, SB, Lee, JS, Mills, G & Cho, JY 2011, 'Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer', PLoS One, vol. 6, no. 9, e24662. https://doi.org/10.1371/journal.pone.0024662
Claerhout, Sofie ; Lim, Jae Yun ; Choi, Woonyoung ; Park, Yun Yong ; Kim, KyoungHyun ; Kim, Sang Bae ; Lee, Ju Seog ; Mills, Gordon ; Cho, Jae Yong. / Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. In: PLoS One. 2011 ; Vol. 6, No. 9.
@article{342db73a22d1419e95ad43ddc7b54335,
title = "Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer",
abstract = "Background: Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.",
author = "Sofie Claerhout and Lim, {Jae Yun} and Woonyoung Choi and Park, {Yun Yong} and KyoungHyun Kim and Kim, {Sang Bae} and Lee, {Ju Seog} and Gordon Mills and Cho, {Jae Yong}",
year = "2011",
month = "9",
day = "9",
doi = "10.1371/journal.pone.0024662",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer

AU - Claerhout, Sofie

AU - Lim, Jae Yun

AU - Choi, Woonyoung

AU - Park, Yun Yong

AU - Kim, KyoungHyun

AU - Kim, Sang Bae

AU - Lee, Ju Seog

AU - Mills, Gordon

AU - Cho, Jae Yong

PY - 2011/9/9

Y1 - 2011/9/9

N2 - Background: Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

AB - Background: Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

UR - http://www.scopus.com/inward/record.url?scp=80052576073&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052576073&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0024662

DO - 10.1371/journal.pone.0024662

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e24662

ER -