Pruszko Magdalena, Milano Elisa, Forcato Mattia, Donzelli Sara, Ganci Federica, Di Agostino Silvia, De Panfilis Simone, Fazi Francesco, Bates David O, Bicciato Silvio, Zylicz Maciej, Zylicz Alicja, Blandino Giovanni, Fontemaggi Giulia
Department of Molecular Biology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland.
EMBO Rep. 2017 Aug;18(8):1331-1351. doi: 10.15252/embr.201643370. Epub 2017 Jun 26.
The abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with a poorly differentiated and aggressive phenotype of mammary carcinomas. This long non-coding RNA (lncRNA) localizes to nuclear speckles, where it interacts with a subset of splicing factors and modulates their activity. In this study, we demonstrate that oncogenic splicing factor SRSF1 bridges MALAT1 to mutant p53 and ID4 proteins in breast cancer cells. Mutant p53 and ID4 delocalize MALAT1 from nuclear speckles and favor its association with chromatin. This enables aberrant recruitment of MALAT1 on VEGFA pre-mRNA and modulation of VEGFA isoforms expression. Interestingly, VEGFA-dependent expression signatures associate with ID4 expression specifically in basal-like breast cancers carrying mutations. Our results highlight a key role for MALAT1 in control of VEGFA isoforms expression in breast cancer cells expressing gain-of-function mutant p53 and ID4 proteins.
丰富的、核内保留的、转移相关的肺腺癌转录本1（MALAT1）与乳腺癌的低分化和侵袭性表型有关。这种长链非编码RNA（lncRNA）定位于核斑点，在那里它与一部分剪接因子相互作用并调节它们的活性。在本研究中，我们证明致癌剪接因子SRSF1在乳腺癌细胞中将MALAT1与突变型p53和ID4蛋白连接起来。突变型p53和ID4使MALAT1从核斑点中脱离，并促进其与染色质的结合。这使得MALAT1异常募集到VEGFA前体mRNA上，并调节VEGFA异构体的表达。有趣的是，VEGFA依赖性表达特征与ID4表达相关，特别是在携带p53突变的基底样乳腺癌中。我们的结果突出了MALAT1在控制表达功能获得性突变型p53和ID4蛋白的乳腺癌细胞中VEGFA异构体表达方面的关键作用。
