USP20 positively regulates tumorigenesis and chemoresistance through ß-catenin stabilization.

ABSTRACT

ß-catenin is a major transcriptional activator of the canonical Wnt/ß-catenin signaling pathway. It is important for a series of biological processes including tissue homeostasis, and embryonic development and is involved in various human diseases. Elevated oncogenic activity of ß-catenin is frequently observed in cancers, which contributes to survival, metastasis and chemo-resistance of cancer cells. However, the mechanism of ß-catenin overexpression in cancers is not well defined. Here we demonstrate that the deubiquitination enzyme USP20 is a new regulator of the Wnt/ß-catenin signaling pathway. Mechanistically, USP20 regulates the deubiquitination of ß-catenin to control its stability, thereby inducing proliferation, invasion and migration of cancer cells. High expression of USP20 correlates with increased ß-catenin protein level in multiple cancer cell lines and patient samples. Moreover, knockdown of USP20 increases ß-catenin polyubiquitination, which enhances ß-catenin turnover and cell sensitivity to chemotherapy. Collectively, our results establish the USP20-ß-catenin axis as a critical regulatory mechanism of canonical Wnt/ß-catenin signaling pathway with an important role in tumorigenesis and chemo response in human cancers.