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 β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-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/β-catenin pathway in colorectal carcinogenesis. Cancer Res; 78(8); 1958-71. ©2018 AACR.
Highlights
Colorectal cancer is the third most common cancer and a major cause of cancer mortality worldwide [1]
Ring finger protein 6 (RNF6) is overexpressed in primary colorectal tumors To identify driver oncogenes deregulated by DNA copy number amplification in colorectal cancer, we performed whole-genome sequencing in paired colorectal cancer and adjacent normal samples, which revealed that RNF6 was one of the top outlier genes overexpressed in colorectal cancer, with a high copy ratio compared with baseline copy ratio (Fig. 1A)
We identified RNF6 as a novel oncogene that is frequently upregulated by gene amplification in primary colorectal cancer (73.5%) in two independent cohorts
Summary
Colorectal cancer is the third most common cancer and a major cause of cancer mortality worldwide [1]. Both the incidence and death rate of colorectal cancer are increasing rapidly and maintaining an upward trend in Asian countries [2]. Chromosomal instability (CIN), including somatic DNA copy number amplification, is a hallmark of cancer and is present in approximately 60% to 70% of sporadic colorectal cancer, and the CIN pathway is usually associated with a stepwise process of "adenoma to carcinoma sequence" [6,7,8]. The somatic copy number alterations (SCNA)–high subtype, which represents nearly 60% of primary colorectal cancers, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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