USP44 suppresses proliferation and enhances apoptosis in colorectal cancer cells by inactivating Wnt/β-catenin pathway via Axin1 deubiquitination.

Colorectal cancer (CRC) is the leading cause of cancer death, and its 5-year survival rate remains unsatisfactory. Recent studies have revealed that ubiquitin-specific protease 44 (USP44) is a cancer suppressor or oncogene depending on the type of neoplasm. However, its role in CRC remains unclear. Here, we found that the USP44 expression level was markedly decreased in CRC, and USP44 overexpression inhibited proliferation while enhancing apoptosis in CRC cells, suggesting that USP44 is a cancer suppressor in CRC. We then investigated if USP44 functioned through regulating the Wnt/beta-catenin pathway. We found that USP44 overexpression increased the Axin1 protein while decreasing beta-catenin, c-myc, and cyclin D1 proteins, suggesting that USP44 inhibited the activation of the Wnt/beta-catenin pathway. Moreover, we found that two Wnt/beta-catenin activators, LiCl and SKL2001, both attenuated oeUSP44-mediated proliferation and apoptosis in CRC cells. Collectively, these data points indicated that USP44 inhibited proliferation while promoting apoptosis in CRC cells by inhibiting the Wnt/beta-catenin pathway. Interestingly, we observed that USP44 overexpression did not affect the Axin1 mRNA level. Further study uncovered that USP44 interacted with Axin1 and reduced the ubiquitination of Axin1. Furthermore, Axin1 knock-down abolished the effects of oeUSP44 on proliferation, apoptosis, and Wnt/beta-catenin activity in CRC cells. Taken together, this study demonstrates that USP44 inhibits proliferation while enhancing apoptosis in CRC cells by inactivating the Wnt/beta-catenin pathway via Axin1 deubiquitination. USP44 is a cancer suppressor in CRC and a potential target for CRC therapy.