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

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...

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Published in:Cellular and molecular life sciences : CMLS Vol. 82; no. 1; pp. 284 - 15
Main Authors: Zhou, Qian, Li, Yanxia, Li, Xiaomei, Zhang, Shujing, Wang, Ying, Li, Zhuoran, Wang, Xia, Li, Yuan, Li, Jingxin, Lu, Chunhua, Shen, Yuemao, Zhao, Baobing
Format: Journal Article
Language:English
Published: Cham Springer International Publishing 19.07.2025
Springer Nature B.V
Springer
Subjects:
5-Fluorouracil
Animals
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer
Cell adhesion & migration
Cell Biology
Cell cycle
Cell growth
Cell Line, Tumor
Cell migration
Cell Movement - genetics
Cell proliferation
Cell Proliferation - genetics
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Disease Progression
DNA biosynthesis
Enzymes
Experiments
Gene expression
Gene Expression Regulation, Neoplastic
Humans
Life Sciences
M6A modification
Medical prognosis
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metastasis
Mice
mRNA stability
Nucleotides
Original
Original Article
p53 Protein
Pleckstrin
Pleckstrin-2
Proteins
RNA Stability - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Senescence
Signal Transduction
Stability
Therapeutic targets
Thymidylate synthase
Thymidylate Synthase - genetics
Thymidylate Synthase - metabolism
Tumor Suppressor Protein p53 - metabolism
Tumorigenesis
Tumors
TYMS
YTHDF2
A modification
YTHDF2
TYMS
M
Pleckstrin-2
Colorectal cancer
M6A modification
ISSN:1420-9071, 1420-682X, 1420-9071
Online Access:Get full text
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Summary: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 m 6 A 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.
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ISSN:1420-9071
1420-682X
1420-9071
DOI:10.1007/s00018-025-05782-x