Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells.
Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells.
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HOXA5 和 STAT3 的协同作用对于人黑色素瘤细胞中 HDAC8 抑制介导的 PD-L1 转录激活至关重要。
DOI：
10.1016/j.jid.2017.11.009
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Jiang CC
中科院分区：
文献类型：
--
作者：
Wang YF;Liu F;Farrely M;Yan XG;Croft A;Liu T;Jin L;Zhang XD;Jiang CC
虽然程序性死亡配体1 （PD-L1）的表达是癌细胞逃避免疫系统的重要机制，但癌细胞中PD-L1的表达通常与患者对抗pd -1/PD-L1抗体治疗的反应有关。然而，PD-L1在黑色素瘤细胞中的表达调控机制尚不清楚。在这里，我们报道了I类组蛋白去乙酰化酶（HDAC） HDAC8通过由转录因子同源盒A5 （HOXA5）和转录信号换能器和激活因子3 （STAT3）组成的转录复合体控制PD-L1的转录激活。抑制HDAC8可上调黑色素瘤细胞中的PD-L1。这是由于PD-L1基因启动子片段的活性增加，该片段富含HOXA5和STAT3的结合位点。事实上，HOXA5或STAT3的下调通过抑制HDAC8消除了PD-L1的上调。此外，在激活PD-L1转录过程中，HOXA5和STAT3在物理上是相关的，并且似乎是相互依赖的。功能研究表明，hdac8介导的PD-L1表达调节参与了抗黑色素瘤T细胞反应的调节。总的来说，这些结果确定了HDAC8是PD-L1表达的重要表观遗传调节剂，这对更好地理解黑色素瘤细胞与免疫系统之间的相互作用具有重要意义。
While the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells are commonly associated with patients' responses to treatment with anti-PD-1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 (HOXA5) and signal transducer and activator of transcription 3 (STAT3). Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both HOXA5 and STAT3. Indeed, knockdown of HOXA5 or STAT3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, HOXA5 and STAT3 were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system.
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影响因子：
23.9
作者：
Qi J;Singh S;Hua WK;Cai Q;Chao SW;Li L;Liu H;Ho Y;McDonald T;Lin A;Marcucci G;Bhatia R;Huang WJ;Chang CI;Kuo YH
通讯作者：
Kuo YH
影响因子：
6.4
作者：
M. Potter;M. Moore;A. Morris
通讯作者：
M. Potter;M. Moore;A. Morris
影响因子：
11.1
作者：
Karwacz, Katarzyna;Bricogne, Christopher;MacDonald, Douglas;Arce, Frederick;Bennett, Clare L.;Collins, Mary;Escors, David
通讯作者：
Escors, David
脓毒症中 PKM2 调节 Warburg 效应并促进 HMGB1 释放
影响因子：
16.6
作者：
Yang, Liangchun;Xie, Min;Yang, Minghua;Yu, Yan;Zhu, Shan;Hou, Wen;Kang, Rui;Lotze, Michael T.;Billiar, Timothy R.;Wang, Haichao;Cao, Lizhi;Tang, Daolin
通讯作者：
Tang, Daolin
DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW