Abstract
Long noncoding RNAs (lncRNAs) are major regulators of many cellular processes including cell cycle progression and tumorigenesis. In this study, we identify a novel lncRNA, MA-linc1, and reveal its effects on cell cycle progression and cancer growth. Inhibition of MA-linc1 expression alters cell cycle distribution, leading to a decrease in the number of G1 cells and a concomitant increase in all other stages of the cell cycle, and in particular G2/M, suggesting its involvement in the regulation of M phase. Accordingly, knock down of MA-linc1 inhibits M phase exit upon release from a mitotic block. We further demonstrate that MA-linc1 predominantly functions in cis to repress expression of its neighboring gene, Purα, which is often deleted in human cancers and whose ectopic expression inhibits cell cycle progression. Knock down of Purα partially rescues the MA-linc1 dependent inhibition of M phase exit. In agreement with its suggested role in M phase, inhibition of MA-linc1 enhances apoptotic cell death induced by the antimitotic drug, Paclitaxel and this enhancement of apoptosis is rescued by Purα knockdown. Furthermore, high levels of MA-linc1 are associated with reduced survival in human breast and lung cancer patients.Taken together, our data identify MA-linc1 as a novel lncRNA regulator of cell cycle and demonstrate its potential role in cancer progression and treatment.
Highlights
Genome-wide transcriptome studies have revealed that mammalian genomes express thousands of long noncoding RNAs, which are > 200 bases in length but lack significant open reading frames [1]
This suggests that an activity common to E2F1 and E2F3 is responsible for regulating MA-linc1 expression
E2Fs are transcription factors best known for their involvement in the timely regulation of protein-coding genes required for cell cycle progression [42]
Summary
Genome-wide transcriptome studies have revealed that mammalian genomes express thousands of long noncoding RNAs (lncRNAs), which are > 200 bases in length but lack significant open reading frames [1]. Thousands of lncRNAs are evolutionarily conserved [2, 3] and exhibit expression patterns that correlate with various cellular processes [2,3,4,5,6]. Other lncRNAs regulate gene expression in trans, mainly by directing the chromatin localization of associated proteins [1, 10, 11]. Their recognition of the target loci can involve recruitment by tethering proteins [12] or formation of RNA:DNA triplexes [13]. Some lncRNAs exert indirect regulatory effects on gene expression by acting as decoys that sequester transcription factors [4, 14] or microRNAs [15,16,17]
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