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

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

doi:10.1101/247429

Cited by 7 publications

(16 citation statements)

References 46 publications

(78 reference statements)

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“…Our published data on reducing tumor growth in xenografted OC bearing mice by delivering toxic siRNAs without affecting normal tissues (22, 45) is consistent with a model in which high amounts of nontoxic miRNAs protect cells from 6mer Seed Tox. This, however, raises the question of why Pt-resistant cells, which apparently also express a higher amount of nontoxic miRNAs, are still susceptible to 6mer Seed Tox.…”

Section: Discussionsupporting

confidence: 86%

The balance between toxic versus nontoxic microRNAs determines platinum sensitivity in ovarian cancer

Patel

Wang

Bartom

et al. 2021

Preprint

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Development of platinum (Pt) resistance is a major barrier to curing ovarian cancer (OC). 6mer seed toxicity is a novel cancer killing mechanism mediated by tumor suppressive miRNAs with a toxic 6mer seed sequence (positions 2-7) through the RNA-induced silencing complex (RISC). The most toxic 6mer seeds are G-rich and kill cells by targeting the 3′ untranslated region of genes critical for cell survival. We now show that treatment of OC cells with Pt leads to an increase in RISC-bound miRNAs carrying toxic 6mer seeds and a decrease in miRNAs with nontoxic seeds. Pt-resistant cells did not exhibit this Pt induced toxicity shift but retained sensitivity to death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in OC patients revealed that miRNA 6mer seed toxicity ratios were predictive of treatment outcomes. Our results suggest that 6mer seed toxicity can be exploited to treat patients with Pt-resistant OC.

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Section: Discussionsupporting

confidence: 86%

The balance between toxic versus nontoxic microRNAs determines platinum sensitivity in ovarian cancer

Patel

Wang

Bartom

et al. 2021

Preprint

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“…We now compare the potency of siGGCAGU to siGGGGGC, the seed of which is present among other miRNAs, in miR-1237-5p. Both siRNAs had a chemically modified passenger strand to prevent loading into the RISC (12,17). When transfected into the OC cell line HeyA8, both siRNAs strongly slowed down cell growth ( Fig.…”

Section: Sigggggc Is Highly Toxic To Multiple Cancer Cells and Prefermentioning

confidence: 99%

Identification of the toxic 6mer seed consensus in human cancer cells

Patel

Bartom

Paudel

et al. 2020

Preprint

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Abstract6mer seed toxicity is a novel anti-cancer mechanism that kills cancer cells by triggering death induced by survival gene elimination (DISE). It is based on si- or shRNAs with a specific G-rich nucleotide composition in position 2-7 of their guide strand. An arrayed screen of 4096 6mer seeds on two human and two mouse cell lines identified a consensus GGGGGC as the most toxic seed. After testing two more cell lines, one human and one mouse, we found that the GGGGGC seed while also toxic to murine cells, is more toxic to human cells, suggesting that the evolution to use of Gs as part of the toxic seeds is still slowly evolving, with Gs more common in the human toxic seeds. While new RNA Seq and bioinformatics analyses suggest that the GGGGGC seed is toxic to cancer cells by targeting GCCCCC seed matches in the 3’ UTR of a set of genes critical for cell survival, we now directly confirm this by identifying a number of genes targeted by this seed. Furthermore, by using a luciferase reporter fused to the 3’ UTR of these genes we confirm direct and specific on-targeting of GCCCCC seed matches. Targeting is strongly attenuated after mutating the GCCCCC seed matches in these 3’ UTRs. Our data confirm that an siRNA containing the GGGGGC seed kills cancer cells through its miRNA like activity and points at artificial miRNAs, si- or shRNAs containing this seed as a potential new cancer therapeutics.

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“…Epidemiological studies conducted in patients with trinucleotide repeat expansion showed a decreased incidence of cancer [ 91 ]. Two hypotheses have been suggested: one proposes the fact that CAG expansion may increase the production of ncRNA that promotes less cancer [ 92 , 93 ].…”

Section: Mechanisms Of Pathogenesis In Hdmentioning

confidence: 99%

“…On the other hand, it increases the expression of the P53 tumor suppressor factor inducing programmed cell death [ 92 , 93 ].…”

Section: Mechanisms Of Pathogenesis In Hdmentioning

confidence: 99%

Huntington disease: Advances in the understanding of its mechanisms

Gatto

Rojas

Persi

et al. 2020

Clinical Parkinsonism & Related Disorders

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Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

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

Cited by 7 publications

References 46 publications

The balance between toxic versus nontoxic microRNAs determines platinum sensitivity in ovarian cancer

The balance between toxic versus nontoxic microRNAs determines platinum sensitivity in ovarian cancer

Identification of the toxic 6mer seed consensus in human cancer cells

Huntington disease: Advances in the understanding of its mechanisms

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