Tetraarsenic oxide affects non-coding RNA transcriptome through deregulating polycomb complexes in MCF7 cells

Abstract

Non-coding RNAs (ncRNAs) play important and diverse roles in mammalian cell biology and pathology. Although the functions of an increasing number of ncRNAs have been identified, the mechanisms underlying ncRNA gene expression remain elusive and are incompletely understood. Here, we investigated ncRNA gene expression in Michigan cancer foundation 7 (MCF7), a malignant breast cancer cell line, on treatment of tetraarsenic oxide (TAO), a potential anti-cancer drug. Our genomic analyses found that TAO up- or down-regulated ncRNA genes genome-wide. A subset of identified ncRNAs with critical biological and clinical functions were validated by real-time quantitative polymerase chain reaction. Intriguingly, these TAO-regulated genes included CDKN2B-AS, HOXA11-AS, SHH, and DUSP5 that are known to interact with or be targeted by polycomb repressive complexes (PRCs). In addition, the PRC subunits were enriched in these TAO-regulated ncRNA genes and TAO treatment deregulated the expression of PRC subunits. Strikingly, TAO decreased the cellular and gene-specific levels of EZH2 expression and H3K27me3. In particular, TAO reduced EZH2 and H3K27me3 and increased transcription at MALAT1 gene. Inhibiting the catalytic activity of EZH2 using GSK343 increased representative TAO-inducible ncRNA genes. Together, our findings suggest that the expression of a subset of ncRNA genes is regulated by PRC2 and that TAO could be a potent epigenetic regulator through PRCs to modulate the ncRNA gene expression in MCF7 cells.