SPOP and HAUSP bidirectionally regulate LZTS2 ubiquitination to modulate the Wnt pathway
Yanran Deng1, Chunfan Xie2, Ran Liu3
1Key Laboratory of Biodiversity Conservation and Bioresource Utilization of Jiangxi Province, College of Life Sciences, Jiangxi Normal University, Nanchang, China.
Cell Death & Disease
|December 23, 2025
Summary
Researchers discovered how SPOP and HAUSP control the stability of LZTS2, a tumor suppressor in colorectal cancer (CRC). This finding reveals a new mechanism regulating CRC cell behavior and offers potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Colorectal cancer (CRC) is a major global health concern, frequently linked to Wnt pathway overactivation.
- LZTS2 acts as a tumor suppressor in CRC by inhibiting the Wnt pathway, but its stability regulation is unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing LZTS2 protein stability in colorectal cancer.
- To investigate the roles of SPOP and HAUSP in controlling LZTS2 ubiquitination and deubiquitination.
- To understand how LZTS2 stability impacts Wnt pathway activity and CRC progression.
Main Methods:
- Investigated the interaction between SPOP, HAUSP, and LZTS2 using biochemical assays.
- Analyzed the ubiquitination and degradation of LZTS2 mediated by SPOP.
- Examined the counteracting effect of HAUSP on LZTS2 degradation.
- Assessed the functional impact of SPOP and HAUSP on LZTS2's tumor-suppressive activities in CRC cells.
Main Results:
- The E3 ligase SPOP targets LZTS2 for ubiquitination-mediated degradation.
- The deubiquitinase HAUSP counteracts SPOP's action, stabilizing LZTS2.
- SPOP and HAUSP competitively bind to LZTS2, leading to bidirectional regulation of its stability.
- SPOP inhibits LZTS2's anti-proliferative and anti-metastatic effects in CRC, while HAUSP enhances them.
- Regulation of LZTS2 stability by SPOP and HAUSP directly influences Wnt pathway activity.
Conclusions:
- A novel regulatory mechanism for LZTS2 stability involving the opposing actions of SPOP and HAUSP has been identified.
- This SPOP-HAUSP-LZTS2 axis plays a critical role in modulating colorectal cancer cell behavior.
- Targeting LZTS2 stability presents a potential therapeutic strategy for colorectal cancer treatment.
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