Date of Graduation
Doctor of Philosophy (PhD)
Min Gyu Lee
MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR, a well-characterized oncogene in human cancers, suppresses the maturation of specific tumor-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of Argonaute2 (Ago2) at Tyr393. 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 (pre-miRNAs) to mature miRNAs. Interestingly, we also identify a long-loop structure in pre-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 posttranslational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumor cells and has potential clinical implications (Shen et al., 2013).
miRNA Maturation; EGFR; Ago2; Hypoxia