The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness.
The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness.
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DOI：
10.1371/journal.pgen.1006752
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发表时间：
2017-04
期刊：
影响因子：
4.5
通讯作者：
Brancolini C
中科院分区：
文献类型：
--
作者：
Di Giorgio E;Franforte E;Cefalù S;Rossi S;Dei Tos AP;Brenca M;Polano M;Maestro R;Paluvai H;Picco R;Brancolini C
MEF2TF在肿瘤发生过程中的作用仍然是个谜。我们在这里阐明，MEF2可以支持促肿瘤或抑制肿瘤的活性，这取决于与共激活物或共抑制物伙伴的相互作用。通过这些相互作用，MEF2监督与基因激活/抑制相关的组蛋白修饰，如H3K4甲基化和H3K27乙酰化。产生MEF2抑制环境的关键开关是IIa类HDAC。在平滑肌肉瘤(LMS)中，MEF2的这种两面性与肿瘤的侵袭性有关。IIa类HDACs在22%的LMS中过度表达，而MEF2、HDAC4和HDAC9的高水平与总存活率呈负相关。HDAC9的敲除通过恢复一些MEF2靶基因的转录熟练程度来抑制LMS细胞的转化表型。HDAC9还协调MEF2靶基因启动子上H3K4me3的去甲基化。此外，我们还证明了IIa类HDAC并不能结合MEF2结合的所有调控元件。因此，在一个细胞中，活跃转录和强烈抑制的MEF2靶基因可以共存。然而，这些被抑制的MEF2-靶点在染色质签名方面是稳定的。总体而言，我们的结果特别是IIa类HDACs和HDAC9，作为LMS治疗干预的可用药靶点。肿瘤的形成过程以转录格局的深刻变化为特征，目的是维持不受控制的细胞生长，抵抗细胞凋亡和转移。MEF2是一个多效性转录因子家族，其在这些变化中的作用是有争议的，因为已有促肿瘤和抑瘤活性的报道。为了阐明这一悖论，我们研究了MEF2在一种侵袭性软组织肉瘤--平滑肌肉瘤(LMS)中的作用。我们发现在LMS细胞中，当MEF2与IIa类HDAC形成复合体时，MEF2成为癌基因。我们已经确定了MEF2靶基因的不同亚类，并观察到HDAC9在MEF2调控的某些但不是全部基因座上将MEF2转化为转录抑制因子。这种转化与MEF2获得致癌特性有关。我们还阐明了一些由MEF2监督的表观遗传重排。综上所述，我们的研究表明，MEF2在癌症中的矛盾作用可以通过它们作为转录激活/抑制因子的双重作用来解释，并为治疗干预打开了新的可能性。
The contribution of MEF2 TFs to the tumorigenic process is still mysterious. Here we clarify that MEF2 can support both pro-oncogenic or tumor suppressive activities depending on the interaction with co-activators or co-repressors partners. Through these interactions MEF2 supervise histone modifications associated with gene activation/repression, such as H3K4 methylation and H3K27 acetylation. Critical switches for the generation of a MEF2 repressive environment are class IIa HDACs. In leiomyosarcomas (LMS), this two-faced trait of MEF2 is relevant for tumor aggressiveness. Class IIa HDACs are overexpressed in 22% of LMS, where high levels of MEF2, HDAC4 and HDAC9 inversely correlate with overall survival. The knock out of HDAC9 suppresses the transformed phenotype of LMS cells, by restoring the transcriptional proficiency of some MEF2-target loci. HDAC9 coordinates also the demethylation of H3K4me3 at the promoters of MEF2-target genes. Moreover, we show that class IIa HDACs do not bind all the regulative elements bound by MEF2. Hence, in a cell MEF2-target genes actively transcribed and strongly repressed can coexist. However, these repressed MEF2-targets are poised in terms of chromatin signature. Overall our results candidate class IIa HDACs and HDAC9 in particular, as druggable targets for a therapeutic intervention in LMS. The tumorigenic process is characterized by profound alterations of the transcriptional landscape, aimed to sustain uncontrolled cell growth, resistance to apoptosis and metastasis. The contribution of MEF2, a pleiotropic family of transcription factors, to these changes is controversial, since both pro-oncogenic and tumor-suppressive activities have been reported. To clarify this paradox, we studied the role of MEF2 in an aggressive type of soft-tissue sarcomas, the leiomyosarcomas (LMS). We found that in LMS cells MEF2 become oncogenes when in complex with class IIa HDACs. We have identified different sub-classes of MEF2-target genes and observed that HDAC9 converts MEF2 into transcriptional repressors on some, but not all, MEF2-regulated loci. This conversion correlates with the acquisition by MEF2 of oncogenic properties. We have also elucidated some epigenetic re-arrangements supervised by MEF2. In summary, our studies suggest that the paradoxical actions of MEF2 in cancer can be explained by their dual role as activators/repressors of transcription and open new possibilities for therapeutic interventions.