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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Vydáno v:	Cellular and molecular life sciences : CMLS Ročník 82; číslo 1; s. 284 - 15
Hlavní autoři:	Zhou, Qian, Li, Yanxia, Li, Xiaomei, Zhang, Shujing, Wang, Ying, Li, Zhuoran, Wang, Xia, Li, Yuan, Li, Jingxin, Lu, Chunhua, Shen, Yuemao, Zhao, Baobing
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Cham Springer International Publishing 19.07.2025 Springer Nature B.V Springer
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1420-9071 1420-682X 1420-9071
DOI:	10.1007/s00018-025-05782-x