EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2

• Published in: Nature (London) Vol. 497; no. 7449; pp. 383 - 387
• Main Authors: Shen, Jia, Xia, Weiya, Khotskaya, Yekaterina B., Huo, Longfei, Nakanishi, Kotaro, Lim, Seung-Oe, Du, Yi, Wang, Yan, Chang, Wei-Chao, Chen, Chung-Hsuan, Hsu, Jennifer L., Wu, Yun, Lam, Yung Carmen, James, Brian P., Liu, Xiuping, Liu, Chang-Gong, Patel, Dinshaw J., Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.05.2013; Nature Publishing Group
• Subjects: 631/337/505; 631/80/86; Apoptosis; Argonaute Proteins - chemistry; Argonaute Proteins - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell adhesion & migration; Cell Hypoxia - genetics; Cell Hypoxia - physiology; Cell Line, Tumor; Cell Survival; Cellular control mechanisms; Crystal structure; Deregulation; ErbB Receptors - metabolism; Female; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Hypoxia; Kinases; letter; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - metabolism; multidisciplinary; Neoplasm Invasiveness; Nucleic Acid Conformation; Observations; Phosphorylation; Phosphotyrosine - metabolism; Prognosis; Protein Binding; Proteins; Ribonuclease III - metabolism; RNA Precursors - chemistry; RNA Precursors - genetics; RNA Precursors - metabolism; Science; Survival Analysis; Tumors; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12080

Epidermal growth factor receptor, the product of a human oncogene, suppresses the maturation of specific tumour-suppressor-like microRNAs in response to hypoxic stress through phosphorylation of argonaute 2. Impact of hypoxia on miRNAs MicroRNA-mediated regulation of gene expression occurs during response to stresses such as hypoxia, a condition found in the centre of a solid tumour. Mien-Chie Hung and colleagues show that the oncogene product EGFR (epidermal growth factor receptor) phosphorylates argonaute 2 (AGO2), a critical factor in the biogenesis of microRNAs, and that this process is enhanced by hypoxia. This modification of AGO2 impairs microRNA processing, but promotes cell survival and invasiveness. Breast cancer patients with higher phospho-AGO2 content show a poorer outcome. MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level 1 . Deregulation of miRNAs has been linked to diverse pathological processes, including cancer 2 , 3 . Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses 4 , such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour 5 . However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth factor receptor (EGFR), which is the product of a well-characterized oncogene in human cancers, suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also identify a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer patients. Our study reveals a previously unrecognized function of EGFR in miRNA maturation and demonstrates how EGFR is likely to function as a regulator of AGO2 through novel post-translational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.