HACE1 is a putative tumor suppressor gene in B-cell lymphomagenesis and is down-regulated by both deletion and epigenetic alterations.
HACE1 is a putative tumor suppressor gene in B-cell lymphomagenesis and is down-regulated by both deletion and epigenetic alterations.
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DOI：
10.1016/j.leukres.2016.04.007
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发表时间：
2016-06-01
影响因子：
2.7
通讯作者：
Jardin, Fabrice
中科院分区：
文献类型：
--
作者：
Bouzelfen, Abdelilah;Alcantara, Marion;Jardin, Fabrice
HECT结构域和锚蛋白重复序列的E3泛素蛋白连接酶1，HACE 1，位于染色体6 q上，编码E3泛素连接酶，并在许多人类肿瘤中下调。在这里，我们报告作为一个候选的肿瘤抑制基因的缺失和表观遗传机制的组合下调。在40%的B细胞淋巴瘤肿瘤中观察到HACE 1缺失。在60%（68/111）的病例和所有检测的B细胞淋巴瘤细胞系中发现了HACE 1启动子CpG 177岛的超甲基化。使用HDAC抑制剂，我们观察到主要是无活性的染色质构象（甲基化H3组蛋白H3 K9 me 2）在HACE 1基因启动子区。我们在拉莫斯和Raji细胞中证明，HACE 1表达的下调与凋亡的显著减少和S期和G2/M期细胞的积累相关。我们的实验表明，在大多数B细胞淋巴瘤中，HACE 1可以作为单倍不足的肿瘤抑制基因，并且可以通过其启动子区域染色质的去乙酰化来下调，这使得HACE 1成为HDAC抑制剂的潜在靶点。
HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1, HACE1, located on chromosome 6q, encodes an E3 ubiquitin ligase and is downregulated in many human tumors. Here, we report HACE1 as a candidate tumor suppressor gene down-regulated by a combination of deletion and epigenetic mechanisms. HACE1 deletions were observed in 40% of B-cell lymphoma tumors. Hypermethylation of the HACE1 promoter CpG177 island was found in 60% (68/111) of cases and in all tested B-cell lymphoma lines. Using HDAC inhibitors, we observed predominantly inactive chromatin conformation (methylated H3 histones H3K9me2) in HACE1 gene promoter region. We demonstrated in Ramos and Raji cells that down-regulation of HACE1 expression was associated with a significant decrease in apoptosis and an accumulation of cells in the S and G2/M phases. Our experiments indicate that HACE1 can act as a haploinsufficient tumor suppressor gene in most B-cell lymphomas and can be downregulated by deacetylation of its promoter region chromatin, which makes HACE1 a potential target for HDAC inhibitors.