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

TL;DR

This study shows that Pleckstrin-2 promotes colorectal cancer by stabilizing a key mRNA, offering a new potential treatment target.

Contribution

PLEK2 is identified as a novel therapeutic target in colorectal cancer through its regulation of TYMS mRNA stability.

Findings

PLEK2 enhances TYMS mRNA stability via YTHDF2 in an m6A-dependent manner.

PLEK2 inhibition reduces CRC cell proliferation and tumor progression in mouse models.

PLEK2 promotes CRC cell migration, invasion, and stemness-like properties.

Abstract

High expression of nucleotide synthetic enzyme thymidylate synthase (TYMS) is responsible for the resistance to fluorouracil (FU) treatment and worse survival in colorectal cancer (CRC). Herein, we revealed that pleckstrin-2 (PLEK2) cooperated with YTHDF2 to enhance TYMS mRNA stability in CRC via an m6A dependent manner. Silencing of PLEK2 led to the degradation of TYMS mRNA that suppressed DNA replication, which activated p53/p21 signaling and consequent inhibition of CRC cell proliferation via the cellular senescence. Additionally, PLEK2 is also required for CRC cell migration, invasion and stemness-like properties. PLEK2 inhibition is sufficient to ameliorate the progression of AOM/DSS-induced CRC. Together, our study identified PLEK2 as a key regulator for the progress of CRC via the regulation of TYMS expression, and demonstrated that PLEK2 is a novel therapeutic target for CRC.

The online version contains supplementary material available at 10.1007/s00018-025-05782-x.

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