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USP6 and circCYFIP2 target oncoprotein GOLPH3 for deubiquitination and induce platinum resistance in colon cancer

Shaojian Chen1, Haibin Zhuang1, Xian Deng1

  • 1Department of General Surgery, the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China.

Biochemical Pharmacology
|May 12, 2024
PubMed

Insights

Ubiquitin-specific protease 6 (USP6) stabilizes GOLPH3, promoting colon adenocarcinoma progression. CircCYFIP2 enhances this interaction, conferring chemoresistance and offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • GOLPH3 is an oncoprotein implicated in colon adenocarcinoma (COAD) progression and chemoresistance.
  • The precise regulation of GOLPH3 protein stability in COAD remains largely unelucidated.

Purpose of the Study:

  • To investigate the role of ubiquitin-specific proteases 6 (USP6) in regulating GOLPH3 protein stability in COAD.
  • To explore the function of circCYFIP2 in the context of DDP-resistance in colon cancer.

Main Methods:

  • Investigated the deubiquitination of GOLPH3 by USP6 in COAD cells.
  • Assessed the impact of USP6 overexpression on COAD cell viability, apoptosis, and tumor growth in vitro and in vivo.
  • Examined the expression of circCYFIP2 in DDP-resistant colon cancer cells.
  • Analyzed the interaction between circCYFIP2, GOLPH3, and USP6.

Main Results:

  • USP6 was found to directly deubiquitinate GOLPH3, enhancing its stability and promoting COAD cell viability and tumor growth.
  • Overexpression of USP6 inhibited apoptosis in COAD cells.
  • CircCYFIP2 exhibited high expression in DDP-resistant colon cancer cells and promoted proliferation.
  • CircCYFIP2 acts as a scaffold, strengthening the GOLPH3-USP6 interaction and conferring DDP resistance.

Conclusions:

  • USP6 deubiquitinates and stabilizes GOLPH3 in COAD, contributing to cancer progression.
  • CircCYFIP2 facilitates USP6-mediated GOLPH3 deubiquitination and platinum resistance.
  • The circCYFIP2/USP6/GOLPH3 pathway presents a novel therapeutic target for overcoming chemoresistance in COAD.
Keywords:
Colon cancerDeubiquitinationGOLPH3Platinum resistanceUSP6circCYFIP2

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