An Epigenetic Mechanism Underlying Chromosome 17p Deletion-Driven Tumorigenesis.
An Epigenetic Mechanism Underlying Chromosome 17p Deletion-Driven Tumorigenesis.
复制标题
染色体 17p 缺失驱动肿瘤发生的表观遗传机制
DOI：
10.1158/2159-8290.cd-20-0336
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发表时间：
2021-01
期刊：
影响因子：
28.2
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Chen M;Chen X;Li S;Pan X;Gong Y;Zheng J;Xu J;Zhao C;Zhang Q;Zhang S;Qi L;Wang Z;Shi K;Ding BS;Xue Z;Chen L;Yang S;Wang Y;Niu T;Dai L;Lowe SW;Chen C;Liu Y
染色体拷贝数变异是癌症的标志。其中，普遍的染色体17 p缺失与不良预后相关，并且比TP 53缺失更能促进肿瘤发生。在这里，我们利用多功能遗传策略，并确定了一个新的17 p肿瘤抑制基因，PHD指蛋白23（PHF 23）。其缺乏损害B细胞分化并促进未成熟的B淋巴母细胞恶性肿瘤。从机制上讲，我们证明PHF 23，一个H3 K4 me 3的读者，直接结合的SIN 3-HDAC复合物通过其N-末端和抑制其对H3 K27 ac的脱乙酰化活性。因此，PHF 23-SIN 3-HDAC（PSH）复合物协调这两个主要的活性组蛋白标记物，用于激活下游TSG和分化相关基因。此外，PSH复合物的失调对于PHF 23缺陷和17 p缺失的肿瘤的发展和维持是必不可少的。因此，我们的研究揭示了一种新的表观遗传调控机制，有助于17 p缺失癌症的病理学，并表明对这种疾病的新易感性。
Chromosome copy number variations are a hallmark of cancers. Among them, the prevalent chromosome 17p deletions are associated with poor prognosis and can promote tumorigenesis more than TP53 loss. Here we utilize multiple functional genetic strategies and identify a new 17p tumor suppressor gene, PHD finger protein 23 (PHF23). Its deficiency impairs B cell differentiation and promotes immature B lymphoblastic malignancy. Mechanistically, we demonstrate that PHF23, an H3K4me3 reader, directly binds the SIN3-HDAC complex through its N-terminus and represses its deacetylation activity on H3K27ac. Thus, the PHF23-SIN3-HDAC (PSH) complex coordinates these two major active histone markers for the activation of downstream TSGs and differentiation-related genes. Further, dysregulation of the PSH complex is essential for the development and maintenance of PHF23 deficient and 17p deleted tumors. Hence, our study reveals a novel epigenetic regulatory mechanism that contributes to the pathology of 17p-deleted cancers and suggests novel susceptibility to this disease.