Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer

Myoung Hee Kang; Hyunji Choi; Masanobu Oshima; Jae Ho Cheong; Seokho Kim; Jung Hoon Lee; Young Soo Park; Hueng Sik Choi; Mi Na Kweon; Chan Gi Pack; Ju Seog Lee; Gordon B. Mills; Seung Jae Myung; Yun Yong Park

doi:10.1038/s41467-018-04244-2

Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer

Myoung Hee Kang, Hyunji Choi, Masanobu Oshima, Jae Ho Cheong, Seokho Kim, Jung Hoon Lee, Young Soo Park, Hueng Sik Choi, Mi Na Kweon, Chan Gi Pack, Ju Seog Lee, Gordon B. Mills, Seung Jae Myung, Yun Yong Park

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Abstract

The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.

Original language	English (US)
Article number	1920
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04244-2
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer",

abstract = "The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.",

author = "Kang, {Myoung Hee} and Hyunji Choi and Masanobu Oshima and Cheong, {Jae Ho} and Seokho Kim and Lee, {Jung Hoon} and Park, {Young Soo} and Choi, {Hueng Sik} and Kweon, {Mi Na} and Pack, {Chan Gi} and Lee, {Ju Seog} and Mills, {Gordon B.} and Myung, {Seung Jae} and Park, {Yun Yong}",

note = "Funding Information: This research was supported by the Ministry of Education (NRF-2017R1A2B4001962 to Y.-Y.P.) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C0972 and HI17C0380 to Y.-Y.P.). We thank the Confocal Microscope core facility at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Science, for support and instrumentation. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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doi = "10.1038/s41467-018-04244-2",

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AU - Kang, Myoung Hee

AU - Choi, Hyunji

AU - Oshima, Masanobu

AU - Cheong, Jae Ho

AU - Kim, Seokho

AU - Lee, Jung Hoon

AU - Park, Young Soo

AU - Choi, Hueng Sik

AU - Kweon, Mi Na

AU - Pack, Chan Gi

AU - Lee, Ju Seog

AU - Mills, Gordon B.

AU - Myung, Seung Jae

AU - Park, Yun Yong

N1 - Funding Information: This research was supported by the Ministry of Education (NRF-2017R1A2B4001962 to Y.-Y.P.) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C0972 and HI17C0380 to Y.-Y.P.). We thank the Confocal Microscope core facility at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Science, for support and instrumentation. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.

AB - The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.

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Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer

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