PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC.
PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC.
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PKM2 诱导的组蛋白 H3 磷酸化有助于 EGF 介导的 HCC 中的 PD-L1 转录
DOI：
10.3389/fphar.2020.577108
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发表时间：
2020
影响因子：
5.6
通讯作者：
Fang D
中科院分区：
文献类型：
--
作者：
Wang X;Liang C;Yao X;Yang RH;Zhang ZS;Liu FY;Li WQ;Pei SH;Ma J;Xie SQ;Fang D
肝癌细胞中程序性死亡配体-1(PD-L1)的高表达通常会抑制T细胞的增殖和功能，导致肿瘤微环境中的免疫抑制。然而，关于PD-L1在肝癌细胞中过表达的机制还很少被描述。在本研究中，我们发现表皮生长因子(EGF)刺激能促进肝癌细胞中PD-L1mRNA和蛋白的表达。抑制表皮生长因子受体(EGFR)可逆转EGF诱导的PD-L1mRNA和蛋白表达。随后，我们还观察到，在EGF刺激下，Ser37位点的丙酮酸激酶亚型M2(PKM2)的磷酸化水平也增加。模拟磷酸化的PKM2 S37D突变体的表达可促进肝癌细胞中PD-L1的表达和H3-Thr11的磷酸化，而抑制PKM2则显著抑制EGF诱导的PD-L1表达和H3-Thr11的磷酸化。此外，组蛋白H3的Thr11突变为丙氨酸抑制了EGF诱导的PD-L1的mRNA和蛋白表达，染色质免疫沉淀(ChIP)实验也表明EGF处理导致PD-L1启动子H3-Thr11的磷酸化增强。在二乙基亚硝胺(DEN)诱导的大鼠肝细胞癌模型中，我们发现磷酸化的EGFR、PKM2的核表达、H3-Thr11的磷酸化以及PD-L1的mRNA和蛋白在肝脏中的表达均高于正常大鼠。综上所述，我们的研究表明，依赖于PKM2的组蛋白H3-Thr11的磷酸化在EGF诱导的肝细胞癌中PD-L1的转录水平上是至关重要的。这些发现可能为肝细胞癌的治疗提供另一种靶点。
High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.
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