The long noncoding MALAT1 RNA is upregulated in cancer tissues and its elevated expression is associated with hyper-proliferation, but the underlying mechanism is poorly understood. We demonstrate that MALAT1 levels are regulated during normal cell cycle progression. Genome-wide transcriptome analyses in normal human diploid fibroblasts reveal that MALAT1 modulates the expression of cell cycle genes and is required for G1/S and mitotic progression. Depletion of MALAT1 leads to activation of p53 and its target genes. The cell cycle defects observed in MALAT1-depleted cells are sensitive to p53 levels, indicating that p53 is a major downstream mediator of MALAT1 activity. Furthermore, MALAT1-depleted cells display reduced expression of B-MYB (Mybl2), an oncogenic transcription factor involved in G2/M progression, due to altered binding of splicing factors on B-MYB pre-mRNA and aberrant alternative splicing. In human cells, MALAT1 promotes cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle–regulated transcription factors. These findings provide mechanistic insights on the role of MALAT1 in regulating cellular proliferation.
The mammalian genome encodes large number of long non protein-coding RNAs (lncRNAs). These lncRNAs are suggested to regulate key biological processes (including cellular proliferation and differentiation), and aberrant expression of these is associated with cancer. However, only a few of these lncRNAs have been functionally validated in biological or disease processes. MALAT1, an abundant nuclear-retained lncRNA, is overexpressed in several cancers, and its elevated expression has been associated with hyper-proliferation and metastasis. However, the underlying mechanism behind this deregulation and its association with cancer is poorly understood. Here, we establish the role of MALAT1 in the cell cycle pathway and propose the molecular mechanism of its function during normal cell cycle progression. MALAT1 RNA levels are differentially regulated and critical for normal cell cycle progression. Depletion of MALAT1 results in cell cycle arrest with significantly reduced cellular proliferation, simultaneously leading to activation of p53 and its target genes. Further, the accurate levels of MALAT1 in the cell are extremely crucial for expression and activity of the oncogenic transcription factor B-MYB, which is involved in G2/M progression. Our data indicates that the cancer-associated MALAT1 RNA regulates cellular proliferation by modulating the expression and/or pre-mRNA processing of cell cycle–regulated transcription factors.