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USP14 promotes colorectal cancer progression by targeting JNK for stabilization

Xue-Hua Du1,2, Shao-Bo Ke3, Xin-Yi Liang2

  • 1School of Medicine, Chongqing University, Chongqing, 400030, China.

Cell Death & Disease
|January 24, 2023
PubMed

Insights

USP14 deubiquitinase stabilizes JNK, promoting colorectal cancer. Inhibiting USP14 reduces tumor growth by downregulating MAPK/JNK signaling, suggesting USP14 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways are crucial in cancer development.
  • The precise mechanisms regulating JNK protein stability through ubiquitination are not fully understood.

Purpose of the Study:

  • To investigate the role of USP14 in regulating MAPK/JNK signaling.
  • To identify USP14 as a deubiquitinase targeting JNK.
  • To evaluate USP14 as a potential therapeutic target in colorectal cancer.

Main Methods:

  • RNA sequencing (RNA-seq) for global gene expression analysis.
  • Luciferase reporter assays for pathway identification.
  • In vitro cell proliferation assays.
  • In vivo colorectal tumorigenesis models.
  • Analysis of USP14 expression in patient samples.

Main Results:

  • USP14 deubiquitinase stabilizes JNK protein, enhancing MAPK/JNK pathway activation.
  • USP14 expression is elevated in colorectal cancer and correlates with JNK levels and downstream gene activity.
  • USP14 knockdown inhibits cancer cell proliferation and colorectal tumor growth.
  • Tumor necrosis factor-alpha (TNF-α) induces USP14, creating a positive feedback loop with JNK.

Conclusions:

  • USP14 promotes colorectal carcinogenesis by stabilizing JNK and activating the MAPK/JNK pathway.
  • USP14 represents a promising therapeutic target for colorectal cancer, particularly in patients with elevated USP14 expression.

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