Wu Xi, Wang Shiyang, Pan Yuwei, Li Mengzhen, Song Manyu, Zhang Hanfu, Deng Min, Yang Xu, Xu Jiuzhi, Zhang Shuo, Zhang Jinhua, Wang Fengchao, Plikus Maksim V, Lv Cong, Yu Lu, Yu Zhengquan
The First Affiliated Hospital of Zhengzhou University, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450052, China.
State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
Adv Sci (Weinh). 2025 Jan;12(3):e2406935. doi: 10.1002/advs.202406935. Epub 2024 Nov 24.
Colorectal cancer (CRC) is the third most common cancer type and the second highest mortality rate among cancers. However, the mechanisms underlying CRC progression remain to be fully understood. In this work, a recently identified mA-modified RNA reader protein Proline-rich Coiled-coil 2a (PRRC2A) is markedly upregulated in CRC, and intestinal epithelium-specific deletion of Prrc2a significantly suppressed tumor cell growth, stemness, and migratory capacity, while its overexpression promoted these behaviors. Through multiomics analysis, PRRC2A directly targeted CSNK1E (encoding CK1ε), maintaining its RNA stability in an mA-dependent manner, and that elevated CK1ε can concomitantly result in activation of the WNT and YAP signaling pathways. Interestingly, PRRC2A is directly regulated by the transcription factor ATF1 in its promoter. In summary, the work reveals a novel mechanism by which mA reader PRRC2A promotes colorectal cancer progression via CK1ε and aberrant upregulation of WNT and YAP signaling. Therefore, PRRC2A and CK1ε can be potential therapeutic targets for treating CRC.
结直肠癌（CRC）是第三大常见癌症类型，也是癌症中死亡率第二高的癌症。然而，CRC进展的潜在机制仍有待充分了解。在这项研究中，一种最近鉴定出的mA修饰RNA阅读器蛋白富含脯氨酸的卷曲螺旋2a（PRRC2A）在CRC中显著上调，肠道上皮特异性缺失Prrc2a可显著抑制肿瘤细胞生长、干性和迁移能力，而其过表达则促进这些行为。通过多组学分析，PRRC2A直接靶向CSNK1E（编码CK1ε），以mA依赖的方式维持其RNA稳定性，并且升高的CK1ε可同时导致WNT和YAP信号通路的激活。有趣的是，PRRC2A在其启动子中直接受转录因子ATF1的调控。总之，这项研究揭示了一种新机制，即mA阅读器PRRC2A通过CK1ε以及WNT和YAP信号的异常上调促进结直肠癌进展。因此，PRRC2A和CK1ε可能是治疗CRC的潜在治疗靶点。
