Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells.
Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells.
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通过 COP1/c-Jun/HDAC3 轴增强 PD-L1 启动子的组蛋白 H3 乙酰化是耐药癌细胞中 PD-L1 表达所必需的
DOI：
10.1186/s13046-020-1536-x
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Yurong Qiu
中科院分区：
文献类型：
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作者：
Haifang Wang;Chen Fu;Jun Du;Hongsheng Wang;Rui He;Xiaofeng Yin;Haiti Li;Xian Li;Hongxia Wang;Kui Li;Lei Zheng;Zongcai Liu;Yurong Qiu
背景耐药是癌症治疗的一个主要障碍，因为它会使癌细胞对化疗不敏感。近年来，耐药后肿瘤免疫格局的变化成为人们关注的焦点。程序性死亡配体-1(PD-L1)是一种免疫抑制因子，可抑制T细胞免疫。有证据表明，获得性化疗耐药与癌细胞中PD-L1表达增加有关。方法采用定量RT-PCR、Western blotting和流式细胞术检测PD-L1在3种耐药细胞系A549/CDDP、MCF7/ADR和HepG2/ADR中的表达，并用T细胞增殖实验检测其功能意义。然后，通过芯片分析和功能得失基因研究，探讨JNK/c-jun、组蛋白H3乙酰化、组蛋白脱乙酰酶3(HDAC3)和E3连接酶COP1在PD-L1升高中的作用。此外，利用小鼠移植瘤模型验证了JNK/c-jun和HDAC3在体内对A549/CDDP细胞PD-L1表达的影响。结果PD-L1在A549/CDDP、MCF7/ADR和HepG2/ADR细胞中的表达显著增加，其主要原因是JNK/c-Jun信号增强。从机制上讲，COP1的减少增加了c-jun的积累，从而抑制了HDAC3的表达，从而促进了PD-L1启动子的组蛋白H3乙酰化。此外，体内可通过抑制JNK/c-jun或过表达HDAC3来抑制PD-L1的表达，从而在体外显著逆转CD3+T细胞的增殖抑制。PD-L1在顺铂耐药的临床非小细胞肺癌组织中的表达显著升高，与c-jun的表达呈正相关，与HDAC3的表达呈负相关。结论通过COP1/c-jun/HDAC3轴增强PD-L1启动子的组蛋白H3乙酰化，是耐药癌细胞PD-L1表达增加的关键。我们的研究揭示了耐药癌细胞中PD-L1增加的一个新的调控网络，并且联合PD-L1靶向策略可以提高耐药癌症中基于T细胞的免疫。
BackgroundDrug resistance is a major obstacle to treating cancers because it desensitizes cancer cells to chemotherapy. Recently, attention has been focused on changes in the tumor immune landscape after the acquisition of drug resistance. Programmed death-ligand-1 (PD-L1) is an immune suppressor that inhibits T cell-based immunity. Evidence has shown that acquired chemoresistance is associated with increased PD-L1 expression in cancer cells. However, the underlying mechanism is still largely unknown.MethodsPD-L1 expression in three drug-resistant A549/CDDP, MCF7/ADR and HepG2/ADR cell lines was detected by qRT-PCR, western blotting and flow cytometry, and a T cell proliferation assay was performed to test its functional significance. Then, the potential roles of JNK/c-Jun, histone H3 acetylation, histone deacetylase 3 (HDAC3) and the E3 ligase COP1 in the PD-L1 increase were explored through ChIP assays and gain- and loss-of-function gene studies. Furthermore, murine xenograft tumor models were used to verify the role of JNK/c-Jun and HDAC3 in PD-L1 expression in A549/CDDP cells in vivo. Finally, the correlations of PD-L1, c-Jun and HDAC3 expression in clinical cisplatin-sensitive and cisplatin-resistant non-small cell lung cancer (NSCLC) tissues were analyzed by immunohistochemistry and Pearson’s correlation coefficient.ResultsPD-L1 expression was significantly increased in A549/CDDP, MCF7/ADR and HepG2/ADR cells and was attributed mainly to enhanced JNK/c-Jun signaling activation. Mechanistically, decreased COP1 increased c-Jun accumulation, which subsequently inhibited HDAC3 expression and thereby enhanced histone H3 acetylation of the PD-L1 promoter. Furthermore, PD-L1 expression could be inhibited by JNK/c-Jun inhibition or HDAC3 overexpression in vivo, which could largely reverse inhibited CD3+T cell proliferation in vitro. PD-L1 expression was significantly increased in the cisplatin-resistant clinical NSCLC samples and positively correlated with c-Jun expression but negatively correlated with HDAC3 expression.ConclusionsEnhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis was crucial for the PD-L1 increase in drug-resistant cancer cells. Our study reveals a novel regulatory network for the PD-L1 increase in drug-resistant cancer cells and that combined PD-L1-targeting strategies could improve T cell-based immunity in drug-resistant cancers.