Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB

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.

长链非编码RNA（long noncoding RNA）MALAT1在癌组织中表达上调，其高表达与细胞过度增殖密切相关，但具体的潜在调控机制仍有待阐明。本研究证实，MALAT1的表达水平在正常细胞周期进程中受到动态调控。对正常人类二倍体成纤维细胞开展的全转录组分析结果显示，MALAT1可调控细胞周期相关基因的表达，且对G1/S期转换及有丝分裂进程至关重要。敲低MALAT1可激活p53及其下游靶基因的转录。在MALAT1敲低细胞中观察到的细胞周期缺陷会随p53表达水平的变化而发生改变，这表明p53是MALAT1发挥功能的核心下游介导因子。此外，由于剪接因子在B-MYB（Mybl2）前体mRNA（pre-mRNA）上的结合模式发生改变，引发异常可变剪接，MALAT1敲低细胞中参与G2/M期进程的致癌转录因子B-MYB（Mybl2）的表达水平显著下调。在人类细胞中，MALAT1通过调控细胞周期相关转录因子的表达及/或前体mRNA加工过程，促进细胞增殖。本研究结果为阐明MALAT1调控细胞增殖的作用机制提供了重要的理论依据。