RT Journal Article
SR Electronic
T1 Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 247429
DO 10.1101/247429
A1 Andrea E. Murmann
A1 Quan Q. Gao
A1 William Putzbach
A1 Monal Patel
A1 Elizabeth T. Bartom
A1 Calvin Law
A1 Bryan Bridgeman
A1 Siquan Chen
A1 Kaylin M. McMahon
A1 C. Shad Thaxton
A1 Marcus E. Peter
YR 2018
UL http://biorxiv.org/content/early/2018/01/12/247429.abstract
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.