2. Academic Validation
  3. SPOP and HAUSP bidirectionally regulate LZTS2 ubiquitination to modulate the Wnt pathway

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

  • Cell Death Dis. 2025 Dec 24. doi: 10.1038/s41419-025-08351-z.
Yanran Deng # 1,  Chunfan Xie # 2,  Ran Liu # 3,  Kaize Ma 4,  Jian Tang 5,  Zizhang Zhou 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Biodiversity Conservation and Bioresource Utilization of Jiangxi Province, College of Life Sciences, Jiangxi Normal University, Nanchang, China.
  • 2 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of Thoracic Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 4 College of Life Sciences, Shandong Agricultural University, Tai'an, China.
  • 5 Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 6 Key Laboratory of Biodiversity Conservation and Bioresource Utilization of Jiangxi Province, College of Life Sciences, Jiangxi Normal University, Nanchang, China. [email protected].
  • 7 College of Life Sciences, Shandong Agricultural University, Tai'an, China. [email protected].
  • # Contributed equally.
PMID: 41436424 DOI: 10.1038/s41419-025-08351-z
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.

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