Functional Importance of Dicer Protein in the Adaptive Cellular Response to Hypoxia

Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5B 1W8, Canada.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2012; 287(34):29003-20. DOI: 10.1074/jbc.M112.373365
Source: PubMed


The processes by which cells sense and respond to ambient oxygen concentration are fundamental to cell survival and function, and they commonly target gene regulatory events. To date, however, little is known about the link between the microRNA pathway and hypoxia signaling. Here, we show in vitro and in vivo that chronic hypoxia impairs Dicer (DICER1) expression and activity, resulting in global consequences on microRNA biogenesis. We show that von Hippel-Lindau-dependent down-regulation of Dicer is key to the expression and function of hypoxia-inducible factor α (HIF-α) subunits. Specifically, we show that EPAS1/HIF-2α is regulated by the Dicer-dependent microRNA miR-185, which is down-regulated by hypoxia. Full expression of hypoxia-responsive/HIF target genes in chronic hypoxia (e.g. VEGFA, FLT1/VEGFR1, KDR/VEGFR2, BNIP3L, and SLC2A1/GLUT1), the function of which is to regulate various adaptive responses to compromised oxygen availability, is also dependent on hypoxia-mediated down-regulation of Dicer function and changes in post-transcriptional gene regulation. Therefore, functional deficiency of Dicer in chronic hypoxia is relevant to both HIF-α isoforms and hypoxia-responsive/HIF target genes, especially in the vascular endothelium. These findings have relevance to emerging therapies given that we show that the efficacy of RNA interference under chronic hypoxia, but not normal oxygen availability, is Dicer-dependent. Collectively, these findings show that the down-regulation of Dicer under chronic hypoxia is an adaptive mechanism that serves to maintain the cellular hypoxic response through HIF-α- and microRNA-dependent mechanisms, thereby providing an essential mechanistic insight into the oxygen-dependent microRNA regulatory pathway.

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    • "Several hypoxiainduced miR, notably miR-210, can stabilise the HIF-1 complex and enhance radioresistance in vitro (Grosso et al, 2013). Third, it is now recognised that hypoxia can downregulate Dicer in vitro and in vivo, shaping global miR expression to maintain the induction of hypoxia-responsive genes (Ho et al, 2012). Hence, the complex regulatory interface between the hypoxic tumour microenvironment and miR expression may be another source of radioresistance during RT. "
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    ABSTRACT: At least half of all cancer patients will receive radiation therapy. Tumour radioresistance, or the failure to control certain tumours with this treatment, can result in locoregional recurrence; thus there is great interest in understanding the underlying biology and developing strategies to overcome this problem. The expanding investigation of microRNA in cancer suggests that these regulatory factors can influence the DNA damage response, the microenvironment and survival pathways, among other processes, and thereby may affect tumour radioresistance. As microRNA are readily detectable in tumours and biofluids, they hold promise as predictive biomarkers for therapy response and prognosis. This review highlights the current insights on the major ways that microRNA may contribute to tumour radiation response and whether their levels reflect treatment success. We conclude by applying the potential framework of future roles of miR in personalised radiotherapy using prostate cancer clinical management as an example.British Journal of Cancer advance online publication, 22 January 2015; doi:10.1038/bjc.2015.6
    Full-text · Article · Jan 2015 · British Journal of Cancer
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    • "Dicer is an RNase III family endoribonuclease that plays an important role in dsRNA and pre-miRNA processing by cleaving these molecules into short dsRNA fragments to produce miRNA and siRNA. With a growing understanding of the important role for miRNA and siRNA in mammalian physiology, it is not surprising that Dicer is essential for normal development [23-28] and for regulation of various physiological and pathological processes, including fertility[29] and neural[30], thyroid[31], cardiac[28], hepatic[32], pancreatic[33], and kidney[34-36] cell function. "
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