Wnt/β-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/β-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer.

Through an shRNA-mediated loss-of-function screen, we identified PTPN14 as a potential tumor suppressor. PTPN14 interacts with yes-associated protein 1 (YAP1), a member of the hippo signaling pathway. We showed that PTPN14 promotes the nucleus-to-cytoplasm translocation of YAP1 during contact inhibition and thus inhibits YAP1 transactivation activity. Interestingly, PTPN14 protein stability was positively controlled by cell density. We identified the CRL2^LRR1(cullin2 RING ubiquitin ligase complex/leucine-rich repeat protein 1) complex as the E3 ligase that targets PTPN14 for degradation at low cell density. Collectively, these data suggest that PTPN14 acts to suppress cell proliferation by promoting cell density-dependent cytoplasmic translocation of YAP1.