Myxoid liposarcoma-associated EWSR1-DDIT3 selectively represses osteoblastic and chondrocytic transcription in multipotent mesenchymal cells.
Myxoid liposarcoma-associated EWSR1-DDIT3 selectively represses osteoblastic and chondrocytic transcription in multipotent mesenchymal cells.
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DOI：
10.1371/journal.pone.0036682
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kimura T
中科院分区：
文献类型：
--
作者：
Suzuki K;Matsui Y;Higashimoto M;Kawaguchi Y;Seki S;Motomura H;Hori T;Yahara Y;Kanamori M;Kimura T
脂肪肉瘤是最常见的软组织肉瘤，粘液样脂肪肉瘤是第二常见的脂肪肉瘤。EWSR1-DDIT3是粘液样脂肪肉瘤特异性染色体易位t(12；22)(q13；q12)产生的嵌合融合蛋白。目前的研究表明，多能间充质细胞是肉瘤的起源。EWSR1-DDIT3在致癌转化过程中对靶细胞表型选择的作用机制尚不清楚。报道分析表明，EWSR1-DDIT3粘液样脂肪肉瘤融合蛋白，而不是其野生型融合蛋白EWSR1和DDIT3，选择性地抑制多潜能间充质细胞系特异性标记基因的转录活性。成骨细胞标志物OPN启动子和软骨细胞标志物COL11a2启动子被抑制，而脂肪细胞标志物PPAR-γ2启动子不受影响。突变分析、瞬时芯片分析以及用曲古抑素A(组蛋白脱乙酰酶的有效抑制剂)或5-氮杂-2‘-脱氧胞苷(一种甲基化抗性胞嘧啶同系物)处理细胞，揭示了上述选择性转录抑制的可能分子机制。第一种是EWSR1-DDIT3融合蛋白的遗传作用，通过其DNA结合域的相互作用，导致与OPN和COL11a2启动子内的功能C/EBP位点结合，进而干扰内源C/EBPβ功能。另一种可能的机制是EWSR1-DDIT3的表观遗传作用，它增强了转录抑制位点的组蛋白去乙酰化、DNA甲基化和组蛋白H3K9三甲基化。我们假设EWSR1-DDIT3介导的转录调控可能通过靶基因特异的遗传和表观遗传转换来调节靶细胞谱系。本研究阐明了EWSR1-DDIT3融合蛋白介导的多潜能间充质细胞表型选择在粘液样脂肪肉瘤发生发展过程中的分子机制。更好地了解这一过程对于阐明融合蛋白介导的致癌肉瘤转化中可能的直接谱系重编程是至关重要的。
Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated. Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2′-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions. This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins.
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DOI：
10.1006/bbrc.1997.7627
发表时间：
1997-11-07
影响因子：
3.1
作者：
Clarke, SL;Robinson, CE;Gimble, JM
通讯作者：
Gimble, JM
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
30.8
作者：
Fuks, F;Burgers, WA;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
5.3
作者：
Hata, K;Nishimura, R;Yoneda, T
通讯作者：
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