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Ubiquitination-Dependent LLGL2 Degradation Drives Colorectal Cancer Progression via THBS3 mRNA Stabilization

Jiayan Huang1,2, Tiantian Zhang1,2, Huimin Li1,2

  • 1State Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 7, 2025
PubMed

Insights

Lethal(2) giant larvae protein homolog 2 (LLGL2) acts as a tumor suppressor in colorectal cancer (CRC). LLGL2 depletion promotes CRC progression by stabilizing thrombospondin 3 (THBS3) mRNA, inhibiting the PI3K-Akt pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Colorectal cancer (CRC) is a leading cause of cancer mortality globally, often characterized by metastasis.
  • The role of Lethal(2) giant larvae protein homolog 2 (LLGL2) in CRC pathogenesis is not fully understood.
  • Dysregulation of LLGL2 is observed in various tumor types.

Purpose of the Study:

  • To elucidate the function of LLGL2 in colorectal cancer.
  • To investigate the molecular mechanisms by which LLGL2 influences CRC progression.
  • To identify potential therapeutic targets for CRC treatment.

Main Methods:

  • RNA sequencing to identify pathways affected by LLGL2.
  • RNA immunoprecipitation sequencing to determine LLGL2 RNA targets.
  • Shotgun mass spectrometry to identify protein interactions.
  • Analysis of MDM2's role in LLGL2 regulation.

Main Results:

  • LLGL2 functions as a tumor suppressor in CRC, with LLGL2 depletion promoting CRC progression.
  • LLGL2 inhibits the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt pathway, thereby suppressing CRC.
  • LLGL2 stabilizes thrombospondin 3 (THBS3) mRNA via interaction with CNOT1, leading to PI3K-Akt pathway inactivation.
  • MDM2 promotes LLGL2 degradation through the proteasomal pathway.

Conclusions:

  • LLGL2 suppresses CRC progression by regulating THBS3 mRNA stability and inhibiting the PI3K-Akt pathway.
  • The MDM2-LLGL2 axis represents a novel regulatory mechanism in CRC.
  • Understanding this pathway offers potential therapeutic strategies for colorectal cancer.
Keywords:
LLGL2PI3K‐AktTHBS3colorectal cancerubquitination

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