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Orlistat targets NEDD8 conjugating enzyme UBC12 for cancer therapy

Mengzhen Shen1, Huihui Li1, Ying Xuan1

  • 1Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China; State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai, PR China.

Pharmacological Research
|May 1, 2026
PubMed

Insights

Orlistat, an anti-obesity drug, uniquely inhibits colorectal cancer (CRC) by targeting UBC12, a key regulator of Wnt signaling. This discovery reveals UBC12 as a novel therapeutic target for treating Wnt-dependent cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Colorectal cancer (CRC) is a leading cause of cancer mortality globally.
  • Oncogenic Wnt signaling is a critical driver of CRC development.
  • Existing treatments for CRC have limitations, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify novel therapeutic targets for colorectal cancer (CRC).
  • To investigate the mechanism by which Orlistat inhibits CRC.
  • To explore the role of UBC12 (UBE2M) in Wnt signaling and CRC.

Main Methods:

  • Utilized biochemical assays, including Isothermal Titration Calorimetry (ITC), to confirm Orlistat binding to UBC12.
  • Investigated Orlistat's effect on UBC12 neddylation activity and its interaction with DCN1.
  • Assessed the impact of UBC12 modulation (overexpression and depletion) on Wnt/β-catenin signaling and CRC cell proliferation.

Main Results:

  • Orlistat directly binds to UBC12 with a dissociation constant (KD) of 678 nM.
  • Orlistat inhibits UBC12's NEDD8-conjugating activity and its interaction with DCN1, suppressing Cullin 1 neddylation.
  • UBC12 overexpression promotes Wnt/β-catenin signaling, while UBC12 depletion inhibits this pathway and abrogates Orlistat's anti-CRC effects.

Conclusions:

  • Identified UBC12 as a novel direct target of Orlistat.
  • Established UBC12 as a key regulator of oncogenic Wnt signaling in CRC.
  • Positioned UBC12 as a promising therapeutic target for Wnt-dependent cancers, with Orlistat as a potential therapeutic agent.
Keywords:
Colorectal cancerDrug repurposingOrlistatUBC12Wnt/β-catenin signaling

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