Rivero S, Ceballos-Chávez M, Bhattacharya S S, Reyes J C
Molecular Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
Cell Therapy and Regenerative Medicine Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Seville, Spain.
Oncogene. 2015 Oct 8;34(41):5264-76. doi: 10.1038/onc.2014.446. Epub 2015 Feb 2.
HMG20A is a high mobility group (HMG) domain containing protein homologous to HMG20B, a core subunit of the Lys-specific demethylase 1/REST co-repressor 1 (LSD1-CoREST) histone demethylase complex. Here, we show that HMG20A can replace HMG20B and, therefore, they are mutually exclusive subunits of the complex. Both proteins interact through a coiled-coil domain with BHC80, another subunit of the LSD1-CoREST complex. To investigate the functional differences between the two proteins, we performed transcriptomic analysis of HMG20A- and HMG20B-depleted cells. Analysis of the misregulated genes in HMG20A-knockdown cells evidenced a high proportion of genes related to the epithelial-to-mesenchymal transition (EMT) process. EMT occurs during embryonic development or during the course of malignant cancer progression and consists in the dynamic and reversible transitions between epithelial and mesenchymal phenotypes. We show that HMG20A together with LSD1 are required for SNAI1-dependent repression of epithelial genes and for (transforming growth factor β) TGF-β-triggered EMT. Importantly, HMG20A-depleted cells displayed reduced binding of LSD1 to epithelial gene promoters and increased methylation of lysine 4 of histone H3, suggesting a role of HMG20A in recruiting or in stabilizing the complex at the chromatin. SNAI1 and the TGF-β-related transcription factor SMAD4 were found to be associated with the LSD1-CoREST complex containing HMG20A. Furthermore, we show that HMG20A-depleted cells displayed reduced motility and invasion activity. Finally, we show that expression of HMG20A correlates positively with mesenchymal markers and negatively with epithelial markers in human tumor samples. Taken together, our data demonstrate that HMG20A is essential for the mesenchymal phenotype.
HMG20A是一种含有高迁移率族（HMG）结构域的蛋白质，与赖氨酸特异性去甲基化酶1/REST共抑制因子1（LSD1-CoREST）组蛋白去甲基化酶复合物的核心亚基HMG20B同源。在此，我们表明HMG20A可以替代HMG20B，因此，它们是该复合物的互斥亚基。这两种蛋白质都通过卷曲螺旋结构域与LSD1-CoREST复合物的另一个亚基BHC80相互作用。为了研究这两种蛋白质之间的功能差异，我们对HMG20A和HMG20B缺失的细胞进行了转录组分析。对HMG20A敲低细胞中失调基因的分析表明，与上皮-间质转化（EMT）过程相关的基因比例很高。EMT发生在胚胎发育过程中或恶性肿瘤进展过程中，包括上皮和间质表型之间的动态和可逆转变。我们表明，HMG20A与LSD1一起是SNAI1依赖性抑制上皮基因和转化生长因子β（TGF-β）触发的EMT所必需的。重要的是，HMG20A缺失的细胞显示LSD1与上皮基因启动子的结合减少，组蛋白H3赖氨酸4的甲基化增加，这表明HMG20A在染色质上招募或稳定该复合物中发挥作用。发现SNAI1和TGF-β相关转录因子SMAD4与含有HMG20A的LSD1-CoREST复合物相关。此外，我们表明HMG20A缺失的细胞显示出运动性和侵袭活性降低。最后，我们表明HMG20A的表达在人类肿瘤样本中与间质标志物呈正相关，与上皮标志物呈负相关。综上所述，我们的数据表明HMG20A对间质表型至关重要。
