Abstract
Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the b-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of b-catenin to TCF4/LEF, triggering Wnt/b-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis. Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/b-catenin pathway in colorectal carcinogenesis.
Original language | English |
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Pages (from-to) | 1958-1971 |
Number of pages | 14 |
Journal | Cancer Research |
Volume | 78 |
Issue number | 8 |
DOIs | |
State | Published - Apr 15 2018 |
Bibliographical note
Publisher Copyright:© 2018 American Association for Cancer Research.
Funding
The authors would like to thank Professor Wei Jia (University of Hawaii Cancer Center) and Professor Xiaoyong Yang (Comparative Medicine and Cellular & Molecular Physiology, Yale University), who helped discuss the project and gave helpful suggestions. This project was supported by RGC-GRF Hong Kong (14163817, 14106145, 14111216); HMRF Hong Kong (03140856); 973 Program China (2013CB531401); The National Key Technology R&D Program (2014BAI09B05); Science and Technology Program Grant, Shenzhen (JCYJ20170413161534162); and Shenzhen Virtual University Park Support Scheme to CUHK Shenzhen Research Institute and CUHK direct grant (to J. Yu). This project was supported by RGC-GRF Hong Kong (14163817, 14106145, 14111216); HMRF Hong Kong (03140856); 973 Program China (2013CB531401); The National Key Technology R&D Program (2014BAI09B05); Science and Technology Program Grant, Shenzhen (JCYJ20170413161534162); and Shenzhen Virtual University Park Support Scheme to CUHK Shenzhen Research Institute and CUHK direct grant (to J. Yu).
Funders | Funder number |
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National Basic Research Program of China (973 Program) | |
CUHK Shenzhen Research Institute | |
HMRF Hong Kong | |
National Key Program for Science and Technology Research and Development | |
RGC-GRF Hong Kong | |
Shenzhen Science and Technology Program | |
Shenzhen Virtual University Park | |
University of Hawaii Cancer Center | |
Yale University | |
Solar Energy Technologies Program | 2014BAI09B05 |
Solar Energy Technologies Program | |
Hong Kong Polytechnic University | 14106145, 14111216, 14163817 |
Hong Kong Polytechnic University | |
Shenzhen Graduate School, Peking University | JCYJ20170413161534162 |
Shenzhen Graduate School, Peking University | |
Chinese University of Hong Kong | |
Changjiang Scholar Program of Chinese Ministry of Education | 2013CB531401 |
Changjiang Scholar Program of Chinese Ministry of Education | |
Health and Medical Research Fund | 03140856 |
Health and Medical Research Fund | |
The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen) |
ASJC Scopus subject areas
- Oncology
- Cancer Research