PIWIL2 belongs to the PIWI protein subfamily and is widely expressed in a variety of tumors. Previous studies have shown that PIWIL2 has the characteristics of oncogene. Recently we reported that PIWIL2 suppresses GSK3beta activity to regulate circadian rhythms through SRC-PI3K-AKT pathway. As GSK3beta is a key part of the beta-catenin destruction complex, it plays a vital role in regulating the degradation of beta-catenin. Besides, the activated beta-catenin/CyclinD1 pathway is involved in the proliferation of tumor cells. It is intriguing to investigate whether PIWIL2 regulates beta-catenin and downstream pathway. In this study, we found that PIWIL2 suppressed GSK3beta induced phosphorylation and ubiquitination of beta-catenin, and thus increased beta-catenin accumulation in the nucleus. By up-regulating beta-catenin and CyclinD1, PIWIL2 can promote cell cycle and proliferation in tumor cells. Taken together, our results revealed a novel function of PIWIL2 in regulating beta-catenin/CyclinD1 pathway in tumor cells, providing a new perspective for PIWIL2 as an oncogene.