Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer

Tatiana Ivanova, Hermioni Zouridis, Yonghui Wu, Lai Ling Cheng, Iain Beehuat Tan, Veena Gopalakrishnan, Chia Huey Ooi, Julian Lee, Luo Qin, Jeanie Wu, Minghui Lee, Sun Young Rha, Dan Huang, Natalia Liem, Khay Guan Yeoh, Wei Peng Yong, Bin Tean Teh, Patrick Tan

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Objective: Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance. Design: 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients. Results: Epigenomic analysis identified bone morphogenetic protein 4 (BMP4 ) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4- expressing GCs also did not exhibit cross resistance to oxaliplatin. Conclusions: BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs.

Original languageEnglish
Pages (from-to)22-23
Number of pages2
JournalGut
Volume62
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1

Fingerprint

Bone Morphogenetic Protein 4
Epigenomics
Cisplatin
Stomach Neoplasms
oxaliplatin
Genes
Epithelial-Mesenchymal Transition
DNA Fingerprinting
Gene Expression Profiling
DNA Methylation
Complementary Therapies
Platinum
Methylation

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Ivanova, T., Zouridis, H., Wu, Y., Cheng, L. L., Tan, I. B., Gopalakrishnan, V., ... Tan, P. (2013). Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut, 62(1), 22-23. https://doi.org/10.1136/gutjnl-2011-301113
Ivanova, Tatiana ; Zouridis, Hermioni ; Wu, Yonghui ; Cheng, Lai Ling ; Tan, Iain Beehuat ; Gopalakrishnan, Veena ; Ooi, Chia Huey ; Lee, Julian ; Qin, Luo ; Wu, Jeanie ; Lee, Minghui ; Rha, Sun Young ; Huang, Dan ; Liem, Natalia ; Yeoh, Khay Guan ; Yong, Wei Peng ; Teh, Bin Tean ; Tan, Patrick. / Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. In: Gut. 2013 ; Vol. 62, No. 1. pp. 22-23.
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abstract = "Objective: Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance. Design: 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients. Results: Epigenomic analysis identified bone morphogenetic protein 4 (BMP4 ) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4- expressing GCs also did not exhibit cross resistance to oxaliplatin. Conclusions: BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs.",
author = "Tatiana Ivanova and Hermioni Zouridis and Yonghui Wu and Cheng, {Lai Ling} and Tan, {Iain Beehuat} and Veena Gopalakrishnan and Ooi, {Chia Huey} and Julian Lee and Luo Qin and Jeanie Wu and Minghui Lee and Rha, {Sun Young} and Dan Huang and Natalia Liem and Yeoh, {Khay Guan} and Yong, {Wei Peng} and Teh, {Bin Tean} and Patrick Tan",
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Ivanova, T, Zouridis, H, Wu, Y, Cheng, LL, Tan, IB, Gopalakrishnan, V, Ooi, CH, Lee, J, Qin, L, Wu, J, Lee, M, Rha, SY, Huang, D, Liem, N, Yeoh, KG, Yong, WP, Teh, BT & Tan, P 2013, 'Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer', Gut, vol. 62, no. 1, pp. 22-23. https://doi.org/10.1136/gutjnl-2011-301113

Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. / Ivanova, Tatiana; Zouridis, Hermioni; Wu, Yonghui; Cheng, Lai Ling; Tan, Iain Beehuat; Gopalakrishnan, Veena; Ooi, Chia Huey; Lee, Julian; Qin, Luo; Wu, Jeanie; Lee, Minghui; Rha, Sun Young; Huang, Dan; Liem, Natalia; Yeoh, Khay Guan; Yong, Wei Peng; Teh, Bin Tean; Tan, Patrick.

In: Gut, Vol. 62, No. 1, 01.01.2013, p. 22-23.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer

AU - Ivanova, Tatiana

AU - Zouridis, Hermioni

AU - Wu, Yonghui

AU - Cheng, Lai Ling

AU - Tan, Iain Beehuat

AU - Gopalakrishnan, Veena

AU - Ooi, Chia Huey

AU - Lee, Julian

AU - Qin, Luo

AU - Wu, Jeanie

AU - Lee, Minghui

AU - Rha, Sun Young

AU - Huang, Dan

AU - Liem, Natalia

AU - Yeoh, Khay Guan

AU - Yong, Wei Peng

AU - Teh, Bin Tean

AU - Tan, Patrick

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Objective: Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance. Design: 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients. Results: Epigenomic analysis identified bone morphogenetic protein 4 (BMP4 ) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4- expressing GCs also did not exhibit cross resistance to oxaliplatin. Conclusions: BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs.

AB - Objective: Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance. Design: 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients. Results: Epigenomic analysis identified bone morphogenetic protein 4 (BMP4 ) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4- expressing GCs also did not exhibit cross resistance to oxaliplatin. Conclusions: BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs.

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Ivanova T, Zouridis H, Wu Y, Cheng LL, Tan IB, Gopalakrishnan V et al. Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut. 2013 Jan 1;62(1):22-23. https://doi.org/10.1136/gutjnl-2011-301113