title: The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cells.
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.
authors: Apoptosis Research Group, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom.
authors: Mark R
authors: MR
authors: Pickard
authors: Apoptosis Research Group, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom.
authors: Gwyn T
authors: GT
authors: Williams
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D009841:Oligonucleotides / Q000235:genetics; D062085:RNA, Long Noncoding / Q000187:drug effects* / Q000235:genetics; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: C561567:GAS5 long non-coding RNA, human; D006728:Hormones; D009841:Oligonucleotides; D062085:RNA, Long Noncoding
keywords: GAS5; apoptosis; breast cancer; lncRNA; oligonucleotide therapy