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The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cells.

Pickard, Mark R.
; 
Williams, Gwyn T.
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Affiliation
Keele University
EPub Date
Publication Date
2016-02-03
Submitted Date
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Chester Medical School
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Abstract
Growth arrest-specific 5 (GAS5) lncRNA promotes apoptosis, and its expression is down-regulated in breast cancer. GAS5 lncRNA is a decoy of glucocorticoid/related receptors; a stem-loop sequence constitutes the GAS5 hormone response element mimic (HREM), which is essential for the regulation of breast cancer cell apoptosis. This preclinical study aimed to determine if the GAS5 HREM sequence alone promotes the apoptosis of breast cancer cells. Nucleofection of hormone-sensitive and -insensitive breast cancer cell lines with a GAS5 HREM DNA oligonucleotide increased both basal and ultraviolet-C-induced apoptosis, and decreased culture viability and clonogenic growth, similar to GAS5 lncRNA. The HREM oligonucleotide demonstrated similar sequence specificity to the native HREM for its functional activity and had no effect on endogenous GAS5 lncRNA levels. Certain chemically modified HREM oligonucleotides, notably DNA and RNA phosphorothioates, retained pro-apoptotic. activity. Crucially the HREM oligonucleotide could overcome apoptosis resistance secondary to deficient endogenous GAS5 lncRNA levels. Thus, the GAS5 lncRNA HREM sequence alone is sufficient to induce apoptosis in breast cancer cells, including triple-negative breast cancer cells. These findings further suggest that emerging knowledge of structure/function relationships in the field of lncRNA biology can be exploited for the development of entirely novel, oligonucleotide mimic-based, cancer therapies.
Citation
Pickard, M. R., & Williams, G. T. (2016). The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cells. Oncotarget, 7(9), 10104-10116. https://doi.org/10.18632/oncotarget.7173
Publisher
Impact Journals
Journal
Oncotarget
Research Unit
URI
http://hdl.handle.net/10034/604377
DOI
10.18632/oncotarget.7173
PubMed ID
26862727
PubMed Central ID
Type
Article
Language
en
Description
Series/Report no.
ISSN
EISSN
1949-2553
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Sponsors
Breast Cancer Now
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https://www.oncotarget.com/article/7173/text/