TY - JOUR
T1 - RNF6 promotes colorectal cancer by activating the Wnt/b-catenin pathway via ubiquitination of TLE3
AU - Liu, Lei
AU - Zhang, Yanquan
AU - Wong, Chi Chun
AU - Zhang, Jingwan
AU - Dong, Yujuan
AU - Li, Xiangchun
AU - Kang, Wei
AU - Chan, Francis K.L.
AU - Sung, Joseph J.Y.
AU - Yu, Jun
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047877665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047877665&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-2683
DO - 10.1158/0008-5472.CAN-17-2683
M3 - Article
C2 - 29374067
AN - SCOPUS:85047877665
SN - 0008-5472
VL - 78
SP - 1958
EP - 1971
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -
