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Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability

Qian Zhou1,2,3, Yanxia Li1,2,3, Xiaomei Li1,2

  • 1Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.

Cellular and Molecular Life Sciences : CMLS
|July 19, 2025
PubMed

Insights

Pleckstrin-2 (PLEK2) enhances thymidylate synthase (TYMS) mRNA stability in colorectal cancer (CRC), promoting tumor growth. Inhibiting PLEK2 triggers TYMS degradation, halting CRC cell proliferation and progression, suggesting PLEK2 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • High thymidylate synthase (TYMS) expression correlates with fluorouracil (FU) resistance and poor survival in colorectal cancer (CRC).
  • Understanding mechanisms regulating TYMS is crucial for developing effective CRC therapies.

Purpose of the Study:

  • To investigate the role of pleckstrin-2 (PLEK2) in regulating TYMS expression and its impact on colorectal cancer progression.
  • To identify PLEK2 as a potential therapeutic target for CRC treatment.

Main Methods:

  • Investigated the interaction between PLEK2 and YTHDF2 in enhancing TYMS mRNA stability via an m6A-dependent manner.
  • Utilized gene silencing techniques to assess the effects of PLEK2 depletion on CRC cells.
  • Evaluated the impact of PLEK2 inhibition on CRC cell proliferation, migration, invasion, and stemness.
  • Assessed the therapeutic efficacy of PLEK2 inhibition in an AOM/DSS-induced CRC mouse model.

Main Results:

  • PLEK2 cooperates with YTHDF2 to stabilize TYMS mRNA in an m6A-dependent manner in CRC.
  • Silencing PLEK2 leads to TYMS mRNA degradation, suppressing DNA replication and inducing p53/p21 signaling, resulting in cellular senescence and inhibited CRC cell proliferation.
  • PLEK2 is essential for CRC cell migration, invasion, and stemness.
  • PLEK2 inhibition ameliorates the progression of AOM/DSS-induced CRC.

Conclusions:

  • PLEK2 is a key regulator of colorectal cancer progression through its control of TYMS expression.
  • Targeting PLEK2 represents a novel therapeutic strategy for colorectal cancer.
Keywords:
Colorectal cancerM6A modificationPleckstrin-2TYMSYTHDF2

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