The transcription factor OpWRKY2 positively regulates the biosynthesis of the anticancer drug camptothecin in Ophiorrhiza pumila

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<jats:title>Abstract</jats:title><jats:p>The limited bioavailability of plant-derived natural products with anticancer activity poses major challenges to the pharmaceutical industry. An example of this is camptothecin, a monoterpene indole alkaloid with potent anticancer activity that is extracted at very low concentrations from woody plants. Recently, camptothecin biosynthesis has been shown to become biotechnologically amenable in hairy-root systems of the natural producer <jats:italic>Ophiorrhiza pumila</jats:italic>. Here, time-course expression and metabolite analyses were performed to identify novel transcriptional regulators of camptothecin biosynthesis in <jats:italic>O. pumila</jats:italic>. It is shown here that camptothecin production increased over cultivation time and that the expression pattern of the WRKY transcription factor encoding gene <jats:italic>OpWRKY2</jats:italic> is closely correlated with camptothecin accumulation. Overexpression of <jats:italic>OpWRKY2</jats:italic> led to a more than three-fold increase in camptothecin levels. Accordingly, silencing of <jats:italic>OpWRKY2</jats:italic> correlated with decreased camptothecin levels in the plant. Further detailed molecular characterization by electrophoretic mobility shift, yeast one-hybrid and dual-luciferase assays showed that OpWRKY2 directly binds and activates the central camptothecin pathway gene <jats:italic>OpTDC</jats:italic>. Taken together, the results of this study demonstrate that OpWRKY2 acts as a direct positive regulator of camptothecin biosynthesis. As such, a feasible strategy for the over-accumulation of camptothecin in a biotechnologically amenable system is presented.</jats:p>

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