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USP22 deubiquitinates and stabilizes ERK1/2 to promote colorectal cancer progression

Guang-Chao Ma1, Hai-Tao Yang1, Gang Xu1,2

  • 1Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming, 650500, China.

Acta Pharmacologica Sinica
|May 17, 2026
PubMed

Insights

Ubiquitin-specific protease 22 (USP22) activates the ERK signaling pathway by stabilizing ERK1/2, promoting colorectal cancer (CRC) growth. Inhibiting USP22 with ACT001 suppressed CRC progression, highlighting USP22-ERK1/2 as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Extracellular signal-regulated kinase 1/2 (ERK1/2) pathway dysregulation is common in colorectal cancer (CRC) and linked to therapeutic resistance.
  • Deubiquitinases (DUBs) regulate protein stability and are implicated in cancer development, making them potential drug targets.
  • Ubiquitin-specific protease 22 (USP22) is implicated in CRC progression, but its precise mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which USP22 contributes to colorectal cancer (CRC) progression.
  • To investigate the relationship between USP22 and the ERK1/2 signaling pathway in CRC.
  • To evaluate the therapeutic potential of targeting USP22 in CRC.

Main Methods:

  • Correlation analysis of USP22 and ERK1/2 expression in CRC tissues.
  • Co-immunoprecipitation assays to determine USP22-ERK1/2 interaction.
  • Western blotting to assess protein ubiquitination and degradation.
  • In vitro and in vivo studies using the USP22 inhibitor ACT001 to evaluate CRC cell growth suppression.

Main Results:

  • USP22 expression positively correlates with ERK1/2 expression in CRC.
  • USP22 directly interacts with ERK1/2 and removes K48 polyubiquitin chains, stabilizing ERK1/2 and activating the ERK signaling pathway.
  • The novel USP22 inhibitor ACT001 promotes ERK1/2 ubiquitination and degradation, leading to suppressed CRC cell growth both in vitro and in vivo.

Conclusions:

  • USP22 stabilizes ERK1/2, activating the ERK pathway and promoting colorectal cancer (CRC) development.
  • Targeting the USP22-ERK1/2 axis with inhibitors like ACT001 shows therapeutic promise for CRC treatment.
  • This study reveals a novel mechanism for ERK1/2 dysregulation in CRC and identifies a potential therapeutic strategy.
Keywords:
ACT001CRCERK1/2USP22

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