PT  - JOURNAL ARTICLE
AU  - Andrea E. Murmann
AU  - Quan Q. Gao
AU  - William Putzbach
AU  - Monal Patel
AU  - Elizabeth T. Bartom
AU  - Calvin Law
AU  - Bryan Bridgeman
AU  - Siquan Chen
AU  - Kaylin M. McMahon
AU  - C. Shad Thaxton
AU  - Marcus E. Peter
TI  - Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells
AID  - 10.1101/247429
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 247429
4099  - http://biorxiv.org/content/early/2018/01/12/247429.short
4100  - http://biorxiv.org/content/early/2018/01/12/247429.full
AB  - 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 complimentary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 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 anti-cancer reagents.