HDAC1 and Klf4 interplay critically regulates human myeloid leukemia cell proliferation.
HDAC1 and Klf4 interplay critically regulates human myeloid leukemia cell proliferation.
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HDAC1 和 Klf4 相互作用关键调节人骨髓性白血病细胞增殖
DOI：
10.1038/cddis.2014.433
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发表时间：
2014-10-23
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
急性髓系白血病（acute myeloid leukemia，AML）是一种复杂的造血干细胞疾病，其发病机制、诊断和治疗尚不清楚。一般的组蛋白去乙酰化酶（HDAC）抑制剂已被用于包括AML在内的血液癌症，但缺乏基因特异性极大地限制了其抗癌作用和临床应用。我们发现HDAC 1表达与Krüppel样因子4（Klf 4）表达呈负相关，HDAC 1水平低的AML患者预后较好。此外，在白血病细胞K562、HL-60和U937中敲低HDAC 1显著增加Klf 4表达并抑制细胞周期进展和细胞增殖，对于HDAC抑制剂（VPA和mocetinostat）发现了类似的结果。另外，Klf 4的过表达或敲低可分别在体外和体内显著阻断HDAC 1过表达或敲低对白血病细胞的作用。机制分析表明，HDAC 1和Klf 4竞争性结合Klf 4的启动子区和相反调节Klf 4在髓性白血病中的表达。HDAC 1与Klf 4的相互作用和相互调节是抑制细胞增殖和诱导细胞周期阻滞的潜在特异性靶点，提示HDAC 1和Klf 4是髓系白血病临床诊断、预后和治疗的潜在新分子标志物和靶点。
Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis. Further, knockdown of HDAC1 in leukemia cells K562, HL-60, and U937 significantly increased Klf4 expression and inhibited cell cycle progression and cell proliferation, similar results were found for HDAC inhibitors (VPA and mocetinostat). Moreover, overexpression or knockdown of Klf4 could markedly block the effects of HDAC1 overexpression or knockdown on leukemia cells in vitro and in vivo, respectively. Mechanistic analyses demonstrated that HDAC1 and Klf4 competitively bound to the promoter region of Klf4 and oppositely regulated Klf4 expression in myeloid leukemia. We identified HDAC1 as a potential specific target for repressing cell proliferation and inducing cell cycle arrest through interplay and modulation of Klf4 expression, suggests that HDAC1 and Klf4 are potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia.
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影响因子：
4.2
作者：
Chen, ZY;Rex, S;Tseng, CC
通讯作者：
Tseng, CC
DOI：
10.1016/s0006-291x(03)01356-1
发表时间：
2003-08-22
影响因子：
3.1
作者：
Ohnishi, S;Ohnami, S;Yoshida, T
通讯作者：
Yoshida, T
影响因子：
4.6
作者：
Guo, Xiaoping;Tang, Yongmin
通讯作者：
Tang, Yongmin
影响因子：
11.5
作者：
Pandya, AY;Talley, LI;Ruppert, JM
通讯作者：
Ruppert, JM
影响因子：
254.7
作者：
Siegel, Rebecca;Naishadham, Deepa;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin