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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
PubMed

Insights

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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