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

Nat Commun. 2018 May 15;9(1):1920. doi: 10.1038/s41467-018-04244-2.

Myoung-Hee Kang ¹ ² ³, Hyunji Choi ⁴, Masanobu Oshima ⁵, Jae-Ho Cheong ⁶, Seokho Kim ⁷, Jung Hoon Lee ⁸, Young Soo Park ⁹, Hueng-Sik Choi ¹⁰, Mi-Na Kweon ², Chan-Gi Pack ¹ ², Ju-Seog Lee ³, Gordon B Mills ³, Seung-Jae Myung ¹¹ ¹² ¹³, Yun-Yong Park ¹⁴ ¹⁵

Affiliations

1 ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
2 Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
3 Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, 77030, USA.
4 Department of Biological Sciences, Dong-A University, Busan, 49315, Republic of Korea.
5 Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, 920-8641, Japan.
6 Department of Surgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
7 Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
8 Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
9 Department of Pathology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
10 National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea.
11 ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. [email protected].
12 Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. [email protected].
13 Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. [email protected].
14 ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. [email protected].
15 Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. [email protected].

PMID: 29765046 DOI: 10.1038/s41467-018-04244-2

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.

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