A PRC2-independent function for EZH2 in regulating rRNA 2′-O methylation and IRES-dependent translation

• Published in: Nature cell biology Vol. 23; no. 4; pp. 341 - 354
• Main Authors: Yi, Yang, Li, Yanqiang, Meng, Qingshu, Li, Qiaqia, Li, Fuxi, Lu, Bing, Shen, Jiangchuan, Fazli, Ladan, Zhao, Dongyu, Li, Chao, Jiang, Weihua, Wang, Rui, Liu, Qipeng, Szczepanski, Aileen, Li, Qianru, Qin, Wei, Weiner, Adam B., Lotan, Tamara L., Ji, Zhe, Kalantry, Sundeep, Wang, Lu, Schaeffer, Edward M., Niu, Hengyao, Dong, Xuesen, Zhao, Wei, Chen, Kaifu, Cao, Qi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2021; Nature Publishing Group
• Subjects: 101/47; 101/58; 13/1; 13/109; 13/51; 13/89; 14/19; 14/28; 14/63; 38/77; 631/337/1645/2570; 631/337/176; 631/337/386/1362; 631/337/574; Biomedical and Life Sciences; Cancer; Cancer Research; Cell Biology; Chromosomal Proteins, Non-Histone - genetics; Development and progression; Developmental Biology; DNA Methylation - genetics; Enhancer of Zeste Homolog 2 Protein - genetics; Fibrillarin; Gene Expression Regulation, Neoplastic; Genes, rRNA - genetics; Genetic aspects; Genetic research; Genetic translation; Health aspects; Homology; Humans; Internal ribosome entry site; Internal Ribosome Entry Sites - genetics; Life Sciences; Lysine; Methylation; Methyltransferase; Multiprotein Complexes - genetics; Neoplasms - genetics; Neoplasms - therapy; Nuclear Proteins - genetics; Nucleoli; Oncogenes; Protein Binding - genetics; Protein Biosynthesis - genetics; Ribonucleoproteins, Small Nucleolar - genetics; Ribosomal RNA; rRNA; Stem Cells; Structure; Transcription; Transferases; Translation; Translation initiation; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-021-00653-6

Dysregulated translation is a common feature of cancer. Uncovering its governing factors and underlying mechanism are important for cancer therapy. Here, we report that enhancer of zeste homologue 2 (EZH2), previously known as a transcription repressor and lysine methyltransferase, can directly interact with fibrillarin (FBL) to exert its role in translational regulation. We demonstrate that EZH2 enhances rRNA 2′- O methylation via its direct interaction with FBL. Mechanistically, EZH2 strengthens the FBL–NOP56 interaction and facilitates the assembly of box C/D small nucleolar ribonucleoprotein. Strikingly, EZH2 deficiency impairs the translation process globally and reduces internal ribosome entry site (IRES)-dependent translation initiation in cancer cells. Our findings reveal a previously unrecognized role of EZH2 in cancer-related translational regulation. Yi et al. report that EZH2 exerts a PRC2-independent function in nucleoli, where it bridges FBL and NOP56 to facilitate rRNA methylation and subsequent IRES-dependent translation.