Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including...

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Veröffentlicht in:EMBO reports 2018-03, Vol.19 (3), p.n/a
Hauptverfasser: Murmann, Andrea E, Gao, Quan Q, Putzbach, William E, Patel, Monal, Bartom, Elizabeth T, Law, Calvin Y, Bridgeman, Bryan, Chen, Siquan, McMahon, Kaylin M, Thaxton, C Shad, Peter, Marcus E
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Sprache:eng
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Zusammenfassung:Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA‐sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR‐based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR‐based siRNAs as a novel form of anticancer reagents. Synopsis Trinucleotide repeat disorders like Huntington's disease show severe neurological pathologies, but are also characterised by reduced cancer susceptibility. siRNAs based on trinucleotide repeats show specific toxicity against cancer cells, explaining the low cancer incidence in triple repeat diseases. CAG and CUG trinucleotide repeat (TNR) derived siRNAs are super toxic to cancer cells. Super toxic siRNAs kill cancer cells by targeting survival genes with sequence complementarity via RNAi. Super toxic siRNAs reduce tumor growth in a murine cancer model without affecting normal tissues. Graphical Abstract Trinucleotide repeat disorders like Huntington's disease show severe neurological pathologies, but are also characterised by reduced cancer susceptibility. siRNAs based on trinucleotide repeats show specific toxicity against cancer cells, explaining the low cancer incidence in triple repeat diseases.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201745336