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

Andrea E. Murmann; Quan Q. Gao; William E. Putzbach; Monal Patel; Elizabeth T. Bartom; Calvin Y. Law; Bryan Bridgeman; Siquan Chen; Kaylin M. Mcmahon; C. Shad Thaxton; Marcus E. Peter

doi:10.15252/embr.201745336

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

Andrea E. Murmann^*, Quan Q. Gao, William E. Putzbach, Monal Patel, Elizabeth T. Bartom, Calvin Y. Law, Bryan Bridgeman, Siquan Chen, Kaylin M. Mcmahon, C. Shad Thaxton, Marcus E. Peter

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e45336
Journal	EMBO Reports
Volume	19
Issue number	3
DOIs	https://doi.org/10.15252/embr.201745336
State	Published - Mar 2018

Funding

We are grateful to Dr. Evangelos Kiskinis for advice on trinucleotide repeat expansion diseases and Sarah Fazal for performing siRNA screens. We would like to thank Johannes Peter for help in creating the movies. The mouse Ago1-4 k.o. embryonic stem cells were a kind gift from Dr. Markus Hafner. This work was funded by training grants T32CA070085 (to M.P.) and T32CA009560 (to W.P. and K.M.M), and R35CA197450 (to M.E.P.). C.S.T. would like to thank the Department of Defense/Air Force Office of Scientific Research (FA95501310192) for grant funding, and grant funding from the National Institutes of Health/National Cancer Institute (R01CA167041). K.M.M acknowledges the Ryan Family, the Malkin Family, the Driskill Family, Chicago Baseball Charities Cancer Fellowship, and The Northwestern University Feinberg School of Medicine Developmental Therapeutic Institute for financial and fellowship support.

Keywords

CAG repeats
RNAi
TLP nanoparticles
cell death
trinucleotide repeats

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/embr.201745336

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title = "Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells",

abstract = "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.",

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author = "Murmann, {Andrea E.} and Gao, {Quan Q.} and Putzbach, {William E.} and Monal Patel and Bartom, {Elizabeth T.} and Law, {Calvin Y.} and Bryan Bridgeman and Siquan Chen and Mcmahon, {Kaylin M.} and Thaxton, {C. Shad} and Peter, {Marcus E.}",

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doi = "10.15252/embr.201745336",

language = "English (US)",

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AU - Gao, Quan Q.

AU - Putzbach, William E.

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AU - Bartom, Elizabeth T.

AU - Law, Calvin Y.

AU - Bridgeman, Bryan

AU - Chen, Siquan

AU - Mcmahon, Kaylin M.

AU - Thaxton, C. Shad

AU - Peter, Marcus E.

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N2 - 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.

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 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.

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KW - TLP nanoparticles

KW - cell death

KW - trinucleotide repeats

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

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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