Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability
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 C...
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| Format: | Article |
| Language: | English |
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Springer
2025-07-01
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| Series: | Cellular and Molecular Life Sciences |
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| Online Access: | https://doi.org/10.1007/s00018-025-05782-x |
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| author | Qian Zhou Yanxia Li Xiaomei Li Shujing Zhang Ying Wang Zhuoran Li Xia Wang Yuan Li Jingxin Li Chunhua Lu Yuemao Shen Baobing Zhao |
| author_facet | Qian Zhou Yanxia Li Xiaomei Li Shujing Zhang Ying Wang Zhuoran Li Xia Wang Yuan Li Jingxin Li Chunhua Lu Yuemao Shen Baobing Zhao |
| author_sort | Qian Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-aee50e0f82294fb1b376d3168698ac07 |
| institution | Kabale University |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
| record_format | Article |
| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-aee50e0f82294fb1b376d3168698ac072025-08-20T03:42:44ZengSpringerCellular and Molecular Life Sciences1420-90712025-07-0182111510.1007/s00018-025-05782-xPleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stabilityQian Zhou0Yanxia Li1Xiaomei Li2Shujing Zhang3Ying Wang4Zhuoran Li5Xia Wang6Yuan Li7Jingxin Li8Chunhua Lu9Yuemao Shen10Baobing Zhao11Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong UniversityAbstract 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.https://doi.org/10.1007/s00018-025-05782-xPleckstrin-2YTHDF2TYMSColorectal cancerM6A modification |
| spellingShingle | Qian Zhou Yanxia Li Xiaomei Li Shujing Zhang Ying Wang Zhuoran Li Xia Wang Yuan Li Jingxin Li Chunhua Lu Yuemao Shen Baobing Zhao Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability Cellular and Molecular Life Sciences Pleckstrin-2 YTHDF2 TYMS Colorectal cancer M6A modification |
| title | Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability |
| title_full | Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability |
| title_fullStr | Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability |
| title_full_unstemmed | Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability |
| title_short | Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability |
| title_sort | pleckstrin 2 promotes the progression of colorectal cancer via ythdf2 mediated tyms mrna stability |
| topic | Pleckstrin-2 YTHDF2 TYMS Colorectal cancer M6A modification |
| url | https://doi.org/10.1007/s00018-025-05782-x |
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