The histone demethylase PHF8 promotes adult acute lymphoblastic leukemia through interaction with the MEK/ERK signaling pathway
The histone demethylase PHF8 promotes adult acute lymphoblastic leukemia through interaction with the MEK/ERK signaling pathway
复制标题
组蛋白去甲基化酶 PHF8 通过与 MEK ERK 信号通路相互作用促进成人急性淋巴细胞白血病
DOI：
10.1016/j.bbrc.2018.01.049
复制
发表时间：
2018-02-12
影响因子：
3.1
通讯作者：
Chen, Chunyan
中科院分区：
文献类型：
--
作者：
Fu, Yue;Yang, Yaling;Chen, Chunyan
成人急性淋巴细胞白血病（ALL）是一种淋巴祖细胞恶性疾病，具有高复发风险和不良预后。因此，需要探索新的致病机制和治疗靶点。组蛋白甲基化是最重要的染色质翻译后修饰之一。在这里，我们发现组蛋白去甲基化酶 PHF8 在大量 ALL 临床标本中高表达，并且 PHF8 表达与 ALL 进展相关。 PHF8 敲低可抑制体外 ALL 细胞的增殖并促进其凋亡，并减弱体内肿瘤的生长。 PHF8 至少部分通过直接结合其启动子来转录上调 MEK/ERK 通路中的关键分子 MEKI，从而激活 MEK/ERK 通路。此外，我们发现 MEK/ERK 通路抑制剂 PD184352 随后抑制 PHF8 表达。因此，PHF8与MEK/ERK通路形成正反馈环，PHF8敲低增强了PD184352在ALL细胞中的杀伤力。总之，本研究确定了 PHF8 在成人 ALL 中的致癌功能，并提出了一种新的疾病干预表观遗传策略。 (C) 2018 Elsevier Inc. 保留所有权利。
Adult acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that is associated with a high risk of relapse and poor prognosis. Thus, novel pathogenic mechanisms and therapeutic targets need to be explored. Histone methylation is one of the most significant chromatin post-translational modifications. Here, we show that the histone demethylase PHF8 is highly expressed in a large number of ALL clinical specimens and that PHF8 expression is associated with ALL progression. PHF8 knockdown inhibits proliferation and promotes the apoptosis of ALL cells in vitro as well as attenuates tumor growth in vivo. PHF8 transcriptionally upregulates MEKI, a key molecule in the MEK/ERK pathway, at least partially by directly binding to its promoter, thereby activating the MEK/ERK pathway. In addition, we found that an inhibitor of the MEK/ERK pathway, PD184352, subsequently suppresses PHF8 expression. Thus, PHF8 forms a positive feedback loop with the MEK/ERK pathway, and PHF8 knockdown enhances the lethality of PD184352 in ALL cells. In conclusion, this study identifies oncogenic functions of PHF8 in adult ALL and suggests a novel epigenetic strategy for disease intervention. (C) 2018 Elsevier Inc. All rights reserved.