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HERC4 suppresses colorectal cancer progression by promoting STAT3 ubiquitination

Lanzhu Jiang1, Kaidi Qin1, Yuan Jin1

  • 1Department of Gastrointestinal Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingbei Branch, No. 26 Chuyuan Avenue, Jingzhou District, Jingzhou, Hubei 434000, China.

Iscience
|June 22, 2026
PubMed

Insights

HERC4 is downregulated in colorectal cancer (CRC), suppressing tumor growth by targeting STAT3 for degradation. This discovery reveals HERC4 as a potential therapeutic target for CRC intervention.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Ubiquitination is a key post-translational modification regulating cellular processes.
  • Dysregulation of the ubiquitin system is linked to cancer development.
  • HECT-type E3 ubiquitin ligase HERC4's role in colorectal cancer (CRC) is unclear.

Purpose of the Study:

  • To investigate the role and mechanism of HERC4 in colorectal cancer.
  • To determine the prognostic significance of HERC4 in CRC patients.

Main Methods:

  • Analysis of HERC4 expression in CRC tissues.
  • In vitro and in vivo functional assays to assess HERC4's effect on CRC cell proliferation.
  • Co-immunoprecipitation and ubiquitination assays to identify HERC4 targets and mechanisms.

Main Results:

  • HERC4 is significantly downregulated in CRC tissues, correlating with poor prognosis.
  • HERC4 suppresses CRC cell proliferation in vitro and in vivo.
  • HERC4 directly interacts with STAT3, promoting its K48-linked polyubiquitination and proteasomal degradation.
  • Lysine 392 (K392) of STAT3 was identified as the specific ubiquitination site targeted by HERC4.

Conclusions:

  • HERC4 functions as a tumor suppressor in colorectal cancer.
  • The HERC4-STAT3 interaction and subsequent STAT3 degradation is a key mechanism in HERC4's tumor-suppressive role.
  • The HERC4-STAT3 axis represents a promising therapeutic target for colorectal cancer treatment.
Keywords:
biochemistrybiological sciencescancer

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