RNF6 promotes colorectal cancer by activating the Wnt/{beta}-catenin pathway via ubiquitination of TLE3

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer (CRC). Previous whole-genome sequencing of CRC clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we show that RNF6 is upregulated in 73.5% (147/200) of CRC patients, and was positively associated with RNF6 gene amplification. Further, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of CRC patients. RNF6 promoted cell growth, cell cycle progression, and epithelial-to-mesenchymal transition in CRC 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.

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