MicroRNAs (
miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of
miRNAs has been linked to diverse
pathological processes, including
cancer. Recent studies have also implicated
miRNAs in the regulation of cellular response to a spectrum of stresses, such as
hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. 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.