GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer

Abstract

Effective control of both cell survival and cell proliferation is critical to the prevention of oncogenesis and to successful cancer therapy. Using functional expression cloning, we have identified GAS5 (growth arrest-specific transcript 5) as critical to the control of mammalian apoptosis and cell population growth. GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers. We have found that, in some cell lines, GAS5 expression induces growth arrest and apoptosis independently of other stimuli. GAS5 transcript levels were significantly reduced in breast cancer samples relative to adjacent unaffected normal breast epithelial tissues. The GAS5 gene has no significant protein-coding potential but expression encodes small nucleolar RNAs (snoRNAs) in its introns. Taken together with the recent demonstration of tumor suppressor characteristics in the related snoRNA U50, our observations suggest that such snoRNAs form a novel family of genes controlling oncogenesis and sensitivity to therapy in cancer.

Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy

“…The transfection of breast cancer cells with GAS5 ESTs promotes apoptosis [9], but it is unclear whether mature GAS5 lncRNA is sufficient to mediate this action, as all the effective GAS5 ESTs contained retained snoRNAs. Therefore, the cell death-promoting activities of mature GAS5 lncRNA (i.e., exons 1 -12 only) and the GAS5-O1 EST (comprises snoRNA U74, 3′ sequence of the first intron and exons 2 -12) were compared in MCF7 cells.…”

“…The lncRNA and small nucleolar RNA (snoRNA) host gene, growth arrest-specific 5 (GAS5), is of particular interest in breast cancer, since its expression is down-regulated in tumour tissue [9], and patient prognosis is related to GAS5 transcript levels [10]. GAS5 is a 5′-terminal oligopyrimidine tract (5′-TOP) gene, and comprises 12 exons which are alternatively spliced to yield two possible mature lncRNAs [11].…”

“…In breast and other cell types, GAS5 inhibits cell proliferation and/or stimulates apoptosis [9,[17][18][19][20][21], i.e., key determinants of cell survival that are often disrupted in cancer [22]. Indeed, elevated GAS5 expression inhibits human breast tumour growth in a xenograft mouse model…”

The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine

“…GAS5 is highly expressed in cells that have arrested growth and can sensitize a cell to apoptosis by regulating the activity of glucocorticoids in response to nutrient starvation. 63,64 GAS5 functions by interacting directly with the DNA-binding sites of the glucocorticoid receptor (GR), a specific class of nuclear receptors, preventing GR interaction with cognate glucocorticoid response elements, thus reducing cell metabolism, 65 thereby in effect acting as a molecular decoy. This may turn out to be an integral component of the regulatory machinery for modulating steroid hormone activity in target tissue.…”

“…Interestingly, GAS5 has also been observed to be downregulated in breast cancer, perhaps to keep cancer cells active even under low-nutrient conditions. 63,64 Further studies are needed to determine the underlying mechanisms of how a lncRNA, once activated, modulates the activity of transcription factor(s) to allow the cells to respond to their environment.…”