Destabilization of DNA G-Quadruplexes by Chemical Environment Changes during Tumor Progression Facilitates Transcription.

J Am Chem Soc

Frontier Institute for Biomolecular Engineering Research (FIBER), ‡Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), and §Graduate School of FIRST, Konan University, 17-1-20 minatojima-minamimachi, Kobe 650-0047, Japan.

Published: January 2018

DNA G-quadruplex formation is highly responsive to surrounding conditions, particularly K concentration. Malignant cancer cells have a much lower K concentration than normal cells because of overexpression of a K channel; thus, G-quadruplexes may be unstable in cancer cells. Here, we physicochemically investigated how changes in intracellular chemical environments in vitro and in cells influence G-quadruplex formation and transcription during tumor progression. In vitro, the stable G-quadruplex formation inhibits transcription in a solution containing 150 mM KCl (normal condition). As K concentration decreases, which decreases G-quadruplex stability, transcript production from templates with G-quadruplex-forming potential increases. In normal cells, the trend in transcript productions was similar to that in in vitro experiments, with transcription efficiency inversely correlated with G-quadruplex stability. Interestingly, higher transcript levels were produced from templates with G-quadruplex-forming potential in Ras-transformed and highly metastatic breast cancer cells (MDA-MB-231) than in nontransformed and control MCF-7 cells. Moreover, the amount of transcript produced from G-quadruplex-forming templates decreased upon addition of siRNA targeting KCNH1 mRNA, which encodes a potassium voltage-gated channel subfamily H member 1 (K10.1). Importantly, G-quadruplex dissociation during tumor progression was observed by immunofluorescence using a G-quadruplex-binding antibody in cells. These results suggest that in normal cells, K ions attenuate the transcription of certain oncogenes by stabilizing G-quadruplex structures. Our findings provide insight into the novel mechanism of overexpression of certain G-rich genes during tumor progression.

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Source
http://dx.doi.org/10.1021/jacs.7b09449DOI Listing

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