Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

William Putzbach, Quan Q. Gao, Monal Patel, Stijn Van Dongen, Ashley Haluck-Kangas, Aishe A. Sarshad, Elizabeth T. Bartom, Kwang Youn A. Kim, Denise M. Scholtens, Markus Hafner, Jonathan C. Zhao, Andrea E. Murmann, Marcus E. Peter*

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences-most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells.

Original languageEnglish (US)
Article numbere29702
JournaleLife
Volume6
DOIs
StatePublished - Oct 24 2017

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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