The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cell lines – towards oligonucleotide therapies?

Hdl Handle:
http://hdl.handle.net/10034/615000
Title:
The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cell lines – towards oligonucleotide therapies?
Authors:
Pickard, Mark R.; Williams, Gwyn T.
Abstract:
Background Growth arrest-specific 5 (GAS5), a non-protein coding gene, encodes snoRNAs and lncRNA; transcript levels are controlled by the mTOR and nonsense-mediated decay pathways. GAS5 lncRNA promotes the apoptosis of breast cells, including triple-negative breast cancer (TNBC) cells, but its expression is down-regulated in breast cancer. Rapalogues enhance GAS5 levels in oestrogen receptor-positive breast cancer cells but not in TNBC cells, so that mTOR inhibitor-independent induction of GAS5 may be more productive in enhancing apoptotic responses to therapies. Notably, GAS5 lncRNA acts by riborepression of glucocorticoid/related receptors; a stem-loop sequence constitutes the GAS5 hormone response element mimic (HREM). The aim of this study was to determine if the GAS5 HREM sequence alone is sufficient to promote the apoptosis of breast cancer cells. Method Cells were nucleofected with a DNA oligonucleotide corresponding to the GAS5 lncRNA HREM; controls received oligonucleotides either with scrambled GAS5 sequence or retaining stem-loop structure but lacking the GAS5 HRE consensus; mock-transfected cells were also studied. Cells were irradiated with ultraviolet-C (UV-C) light at 20 h post-transfection to induce apoptosis. Culture viability and apoptosis were assessed and cellular GAS5 levels were determined by RT-qPCR. Results The basal apoptotic rate almost doubled in MCF7 and MDA-MB-231 cells transfected with the HREM oligonucleotide compared with controls. This effect was apparent at 20 h post­-transfection, and a corresponding decrease was observed in culture viability. The HREM sequence also enhanced UV-C-induced apoptosis in an additive manner in both cell lines. Endogenous GAS5 lncRNA expression was unaffected by transfection of the HREM sequence. Conclusion The GAS5 lncRNA HREM is sufficient to induce apoptosis in breast cancer cells, including TNBC cells. This study serves as an exemplar of how emerging knowledge of biologically important lncRNAs may be exploited towards the development of novel oncotherapeutic agents.
Affiliation:
Keele University, United Kingdom
Citation:
Pickard, M., & Williams, G. (2014). The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cell lines – towards oligonucleotide therapies? Paper presented at the NCRI Cancer Conference 2014.
Publisher:
NCRI Cancer Conference 2014 Abstracts
Publication Date:
2014
URI:
http://hdl.handle.net/10034/615000
Additional Links:
http://abstracts.ncri.org.uk/abstract/the-hormone-response-element-mimic-sequence-of-gas5-lncrna-is-sufficient-to-induce-apoptosis-in-breast-cancer-cell-lines-towards-oligonucleotide-therapies-3/
Type:
Meetings and Proceedings
Language:
en
Appears in Collections:
Institute of Medicine

Full metadata record

DC FieldValue Language
dc.contributor.authorPickard, Mark R.en
dc.contributor.authorWilliams, Gwyn T.en
dc.date.accessioned2016-06-29T08:37:30Z-
dc.date.available2016-06-29T08:37:30Z-
dc.date.issued2014-
dc.identifier.citationPickard, M., & Williams, G. (2014). The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cell lines – towards oligonucleotide therapies? Paper presented at the NCRI Cancer Conference 2014.en
dc.identifier.otherNA-
dc.identifier.urihttp://hdl.handle.net/10034/615000-
dc.description.abstractBackground Growth arrest-specific 5 (GAS5), a non-protein coding gene, encodes snoRNAs and lncRNA; transcript levels are controlled by the mTOR and nonsense-mediated decay pathways. GAS5 lncRNA promotes the apoptosis of breast cells, including triple-negative breast cancer (TNBC) cells, but its expression is down-regulated in breast cancer. Rapalogues enhance GAS5 levels in oestrogen receptor-positive breast cancer cells but not in TNBC cells, so that mTOR inhibitor-independent induction of GAS5 may be more productive in enhancing apoptotic responses to therapies. Notably, GAS5 lncRNA acts by riborepression of glucocorticoid/related receptors; a stem-loop sequence constitutes the GAS5 hormone response element mimic (HREM). The aim of this study was to determine if the GAS5 HREM sequence alone is sufficient to promote the apoptosis of breast cancer cells. Method Cells were nucleofected with a DNA oligonucleotide corresponding to the GAS5 lncRNA HREM; controls received oligonucleotides either with scrambled GAS5 sequence or retaining stem-loop structure but lacking the GAS5 HRE consensus; mock-transfected cells were also studied. Cells were irradiated with ultraviolet-C (UV-C) light at 20 h post-transfection to induce apoptosis. Culture viability and apoptosis were assessed and cellular GAS5 levels were determined by RT-qPCR. Results The basal apoptotic rate almost doubled in MCF7 and MDA-MB-231 cells transfected with the HREM oligonucleotide compared with controls. This effect was apparent at 20 h post­-transfection, and a corresponding decrease was observed in culture viability. The HREM sequence also enhanced UV-C-induced apoptosis in an additive manner in both cell lines. Endogenous GAS5 lncRNA expression was unaffected by transfection of the HREM sequence. Conclusion The GAS5 lncRNA HREM is sufficient to induce apoptosis in breast cancer cells, including TNBC cells. This study serves as an exemplar of how emerging knowledge of biologically important lncRNAs may be exploited towards the development of novel oncotherapeutic agents.en
dc.language.isoenen
dc.publisherNCRI Cancer Conference 2014 Abstractsen
dc.relation.urlhttp://abstracts.ncri.org.uk/abstract/the-hormone-response-element-mimic-sequence-of-gas5-lncrna-is-sufficient-to-induce-apoptosis-in-breast-cancer-cell-lines-towards-oligonucleotide-therapies-3/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectGAS5en
dc.subjectlncRNAen
dc.subjectApoptosisen
dc.subjectBreast canceren
dc.titleThe hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cell lines – towards oligonucleotide therapies?en
dc.typeMeetings and Proceedingsen
dc.contributor.departmentKeele University, United Kingdomen
dc.date.accepted2014-07-01-
or.grant.openaccessYesen
rioxxterms.funderUnfundeden
rioxxterms.identifier.projectUnfundeden
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2014-
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