Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class histone deacetylases
Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class histone deacetylases
复制标题
纯姜黄素通过抑制类组蛋白脱乙酰酶增加骨髓增生性肿瘤中 SOCS1 和 SOCS3 的表达
DOI：
10.1093/carcin/bgt070
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发表时间：
2013-07-01
期刊：
影响因子：
4.7
通讯作者：
Gao, Shen-meng
中科院分区：
文献类型：
--
作者：
Chen, Chi-qi;Yu, Kang;Gao, Shen-meng
细胞因子信号传导抑制因子SOCS 1和SOCS 3是Janus激酶2/转录信号传导的信号转导和激活因子的重要负调节因子，其在骨髓增生性肿瘤（MPN）和白血病中被组成性激活。姜黄素已被证明具有抗癌活性，通过不同的机制。然而，姜黄素是否能够调节SOCS 1和SOCS 3的表达仍然是未知的。在此，我们发现姜黄素通过触发K562和HEL细胞中SOCS 1和SOCS 3启动子区域的组蛋白乙酰化来提高SOCS 1和SOCS 3的表达。姜黄素作为一种新型的组蛋白脱乙酰酶（HDAC）抑制剂，能抑制HDAC酶活性，降低HDAC 1、3和8的水平，但对HDAC 2无影响。通过小干扰RNA敲低HDAC 8显著提高SOCS 1和SOCS 3的表达。此外，HDAC 8的异位表达降低了SOCS 1和SOCS 3的水平。因此，HDAC 8在姜黄素对SOCS 1和SOCS 3的调节中起重要作用。此外，HDAC的抑制剂阿司他丁A（TSA）增加了SOCS 1和SOCS 3的水平。此外，姜黄素增加SOCS 1和SOCS 3的转录水平，并显着抑制MPN患者造血祖细胞的克隆形成活性。最后，姜黄素显着抑制HDAC活性，并降低原代MPN细胞中HDAC 8水平。综上所述，我们的数据揭示了SOCS 1和SOCS 3通过姜黄素抑制HDAC活性（特别是HDAC 8）的调节机制。因此，作为一种相对无毒的药物，姜黄素可能在MPN的临床治疗中提供治疗优势。
Suppressors of cytokine signaling, SOCS1 and SOCS3, are important negative regulators of Janus kinase 2/signal transducers and activators of transcription signaling, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Curcumin has been shown to possess anticancer activity through different mechanisms. However, whether curcumin can regulate the expression of SOCS1 and SOCS3 is still unknown. Here, we found that curcumin elevated the expression of SOCS1 and SOCS3 via triggering acetylation of histone in the regions of SOCS1 and SOCS3 promoter in K562 and HEL cells. As a novel histone deacetylases (HDACs) inhibitor, curcumin inhibited HDAC enzyme activities and decreased the levels of HDAC1, 3 and 8 but not HDAC2. Knockdown of HDAC8 by small interfering RNA markedly elevated the expression of SOCS1 and SOCS3. Moreover, ectopic expression of HDAC8 decreased the levels of SOCS1 and SOCS3. Thus, HDAC8 plays an important role in the modulation of SOCS1 and SOCS3 by curcumin. Also, trichostatin A (TSA), an inhibitor of HDACs, increased the levels of SOCS1 and SOCS3. Furthermore, curcumin increased the transcript levels of SOCS1 and SOCS3 and significantly inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Finally, curcumin markedly inhibited HDAC activities and decreased HDAC8 levels in primary MPN cells. Taken together, our data uncover a regulatory mechanism of SOCS1 and SOCS3 through inhibition of HDAC activity (especially HDAC8) by curcumin. Thus, being a relative non-toxic agent, curcumin may offer a therapeutic advantage in the clinical treatment for MPNs.