SPOP and HAUSP bidirectionally regulate LZTS2 ubiquitination to modulate the Wnt pathway

Abstract Colorectal cancer (CRC) is a highly deadly disease worldwide, often characterized by the overactivation of the Wnt pathway. LZTS2 is known to be a tumor suppressor by negatively regulating the Wnt pathway in CRC. However, the mechanisms that control the stability of LZTS2 are not fully understood. In this study, we find that the E3 ligase SPOP promotes ubiquitination-mediated degradation of LZTS2, which is counteracted by the deubiquitinase HAUSP. SPOP and HAUSP compete for binding to the same region of LZTS2, leading to bidirectional regulation of LZTS2 stability. The regulation ultimately impacts the activity of the Wnt pathway. Furthermore, functional analyses reveal that SPOP hinders the tumor-suppressive effects of LZTS2 on CRC cell proliferation and metastasis, whereas HAUSP enhances LZTS2’s anti-tumor activity in CRC cells. Taken together, these findings uncover a novel regulatory mechanism of LZTS2 stability, where SPOP and HAUSP play crucial roles in determining the behavior of CRC cells by balancing the ubiquitination and deubiquitination of LZTS2. This discovery may offer new strategies for utilizing LZTS2 as a potential therapeutic target for cancer treatment.