Trichostatin A, a histone deacetylase inhibitor, suppresses JAK2/STAT3 signaling via inducing the promoter‐associated histone acetylation of SOCS1 and SOCS3 in human colorectal cancer cells
Trichostatin A, a histone deacetylase inhibitor, suppresses JAK2/STAT3 signaling via inducing the promoter‐associated histone acetylation of SOCS1 and SOCS3 in human colorectal cancer cells
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DOI：
10.1002/mc.20777
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发表时间：
2012-02
影响因子：
4.6
通讯作者：
H. Xiong;W. Du;Yan-jie Zhang;Jie Hong;Wenyu Su;Jie-ting Tang;Ying-chao Wang;Rong Lu;J. Fang
中科院分区：
文献类型：
--
作者：
H. Xiong;W. Du;Yan-jie Zhang;Jie Hong;Wenyu Su;Jie-ting Tang;Ying-chao Wang;Rong Lu;J. Fang
异常的Janus激酶/信号转导子和转录激活子（JAK/STAT）信号传导参与了几种癌症的肿瘤发生。细胞因子信号传导抑制因子（SOCS）基因和含SH 2的蛋白酪氨酸磷酸酶1（SHP 1）蛋白是JAK/STAT信号传导的负调节因子，已被报道具有肿瘤抑制功能。然而，在结直肠癌（CRC）细胞中，调节SOCS和SHP 1基因的机制以及JAK/STAT信号通路异常的原因在很大程度上仍然未知。目前的研究表明，组蛋白脱乙酰酶（HDAC）抑制剂阿司他丁A（TSA），导致与SOCS 1和SOCS 3启动子相关的组蛋白的超乙酰化，但不是CRC细胞中的SHP 1启动子。这表明组蛋白修饰参与了SOCS 1和SOCS 3的调控。此外，使用TSA实现了SOCS 1和SOCS 3表达的上调，其还显著下调CRC细胞中的JAK 2/STAT 3信号传导。我们还证明TSA抑制CRC细胞的生长，并通过调节JAK 2/STAT 3信号转导的下游靶点，包括Bcl-2，survivin和p16 ink 4a，诱导G1细胞周期阻滞和凋亡。因此，我们的数据表明，TSA可能通过诱导组蛋白修饰诱导SOCS 1和SOCS 3表达，从而抑制CRC细胞中的JAK 2/STAT 3信号传导。这些结果还建立了JAK 2/STAT 3信号传导的抑制与TSA在CRC细胞中的抗癌作用之间的机制联系。摩尔巨蟹座© 2011 Wiley Periodicals，Inc.
Aberrant janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is involved in the oncogenesis of several cancers. Suppressors of cytokine signaling (SOCS) genes and SH2‐containing protein tyrosine phosphatase 1 (SHP1) proteins, which are negative regulators of JAK/STAT signaling, have been reported to have tumor suppressor functions. However, in colorectal cancer (CRC) cells, the mechanisms that regulate SOCS and SHP1 genes, and the cause of abnormalities in the JAK/STAT signaling pathway, remain largely unknown. The present study shows that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, leads to the hyperacetylation of histones associated with the SOCS1 and SOCS3 promoters, but not the SHP1 promoter in CRC cells. This indicates that histone modifications are involved in the regulation of SOCS1 and SOCS3. Moreover, upregulation of SOCS1 and SOCS3 expression was achieved using TSA, which also significantly downregulated JAK2/STAT3 signaling in CRC cells. We also demonstrate that TSA suppresses the growth of CRC cells, and induces G1 cell cycle arrest and apoptosis through the regulation of downstream targets of JAK2/STAT3 signaling, including Bcl‐2, survivin and p16ink4a. Therefore, our data demonstrate that TSA may induce SOCS1 and SOCS3 expression by inducing histone modifications and consequently inhibits JAK2/STAT3 signaling in CRC cells. These results also establish a mechanistic link between the inhibition of JAK2/STAT3 signaling and the anticancer action of TSA in CRC cells. Mol. Carcinog. © 2011 Wiley Periodicals, Inc.