Zhong Longhua, Wu Jingxun, Zhou Bingqian, Kang Jiapeng, Wang Xicheng, Ye Feng, Lin Xiaoting
Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, P. R. China.
Department of Medical Oncology, Zhangzhou Municipal Hospital, Zhangzhou Municipal Hospital Affiliated of Fujian Medical University, Zhangzhou, P. R. China.
NPJ Precis Oncol. 2024 Oct 25;8(1):243. doi: 10.1038/s41698-024-00737-0.
ALYREF can recognize 5-methylcytosine (m5C) decoration throughout RNAs to regulate RNA metabolism. However, its implications in cancer and precise regulatory mechanisms remain largely elusive. Here, we demonstrated that ALYREF supported colorectal cancer (CRC) growth and migration. Integrated analysis of ALYREF-RIP-Bis-seq and transcriptome profiles identified ribosomal protein S6 kinase B2 (RPS6KB2) and regulatory-associated protein of mTOR (RPTOR) as ALYREF's possible downstream effectors. Mechanistically, ALYREF formed a complex with ELAV like RNA binding protein 1 (ELAVL1) to cooperatively promote m5C recognition and nuclear export of the two mRNAs. Moreover, ALYREF protein was highly expressed in tumor tissues of CRC patients, which predicted their poor prognosis. E2F transcription factor 6 (E2F6)-mediated transactivation gave a molecular insight into ALYREF overexpression. Collectively, ALYREF recruits ELAVL1 to collaboratively facilitate m5C recognition and nuclear export of RPS6KB2 and RPTOR transcripts for colorectal tumorigenesis, providing RNA m5C methylation as promising therapeutic targets and prognostic biomarkers for CRC.
ALYREF能够识别RNA上的5-甲基胞嘧啶（m5C）修饰，从而调节RNA代谢。然而，其在癌症中的作用及精确调控机制仍不清楚。在此，我们证明了ALYREF促进结直肠癌（CRC）的生长和迁移。对ALYREF-RIP-Bis-seq和转录组图谱的综合分析确定核糖体蛋白S6激酶B2（RPS6KB2）和mTOR调节相关蛋白（RPTOR）为ALYREF可能的下游效应分子。机制上，ALYREF与ELAV样RNA结合蛋白1（ELAVL1）形成复合物，协同促进这两种mRNA的m5C识别和核输出。此外，ALYREF蛋白在CRC患者的肿瘤组织中高表达，预示其预后不良。E2F转录因子6（E2F6）介导的反式激活为ALYREF的过表达提供了分子层面的见解。总之，ALYREF招募ELAVL1协同促进RPS6KB2和RPTOR转录本的m5C识别和核输出，从而促进结直肠癌发生，为CRC提供了有前景的治疗靶点和预后生物标志物——RNA m5C甲基化。
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