한빛사논문
인제대학교 의과대학
Joo Mi Yi 1,*,†, Tae-Hong Kang 2, Yu Kyeong Han 1, Ha Young Park 3, Ju Hwan Yang 4, Jin-Han Bae 5, Jung-Soo Suh 5, Tae-Jin Kim 5, Joong-Gook Kim 6, Yan-Hong Cui 7,8, Hiromu Suzuki 9, Kohei Kumegawa 10, Sung Joo Kim 11, Yi Zhao 12, In Ja Park 13, Seung-Mo Hong 14, Joon-Yong Chung 15 & Su-Jae Lee 16,*,†
1Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, South Korea
2Department of Biological Science, Dong-A University, Busan, South Korea
3Department of Pathology, College of Medicine, Inje University, Busan, South Korea
4Department of Physiology and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University Medical School, Jinju, South Korea
5Department of Integrated Biological Science, College of Natural Sciences, Pusan National University, Busan, South Korea
6Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, South Korea
7Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, South Korea
8Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL, USA
9Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
10Cancer Cell Diversity Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, Tokyo, Japan
11Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, South Korea
12Institute for Translation Medicine, Qingdao University, Qingdao, China
13Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
14Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
15Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
16Fibrosis & Cancer Targeting Biotechnology, Seoul, South Korea
*Corresponding author: correspondence to Joo Mi Yi or Su-Jae Lee
†These authors contributed equally to this work
Abstract
While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/β-catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL-mediated oncogenic β-catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic β-catenin, and reducing its cytoplasmic levels in a GSK3β- and β-TrCP-independent manner, indicating that NEURL-β-catenin interactions can lead to a disruption of the canonical Wnt/β-catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/β-catenin signalling.
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