Fu Yue, Yang Yaling, Wang Xiaoming, Yin Xiaolin, Zhou Minran, Wang Siqi, Yang Lin, Huang Tao, Xu Man, Chen Chunyan
Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, PR China.
Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, Shandong, PR China.
Biochem Biophys Res Commun. 2018 Feb 12;496(3):981-987. doi: 10.1016/j.bbrc.2018.01.049. Epub 2018 Jan 9.
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 MEK1, 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.
成人急性淋巴细胞白血病（ALL）是一种淋巴祖细胞的恶性疾病，与高复发风险和不良预后相关。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。在此，我们表明组蛋白去甲基化酶PHF8在大量ALL临床标本中高表达，且PHF8表达与ALL进展相关。敲低PHF8可在体外抑制ALL细胞增殖并促进其凋亡，在体内也可减弱肿瘤生长。PHF8至少部分通过直接结合MEK1（MEK/ERK途径中的关键分子）的启动子，转录上调MEK1，从而激活MEK/ERK途径。此外，我们发现MEK/ERK途径抑制剂PD184352随后可抑制PHF8表达。因此，PHF8与MEK/ERK途径形成正反馈环，敲低PHF8可增强PD184352对ALL细胞的致死性。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。
