A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma
A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma
复制标题
一种新型 IFNα 诱导的长非编码 RNA 通过中断头颈鳞状细胞癌中的 H3K27 乙酰化来负向调节免疫抑制
DOI：
10.1186/s12943-019-1123-y
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发表时间：
2020-01-06
期刊：
影响因子：
37.3
通讯作者：
Jin, Shufang
中科院分区：
文献类型：
--
作者：
Ma, Hailong;Chang, Hanyue;Jin, Shufang
干扰素α（IFN α）是头颈部鳞状细胞癌（HNSCC）免疫抑制的公认调节因子，而长链非编码RNA（lncRNA）在免疫抑制中的作用在很大程度上仍然未知。方法采用lncRNA测序技术筛选IFN α刺激下差异表达的lncRNA。本研究通过体内外实验研究lncRNA在HNSCC中的免疫抑制作用及其机制。结果我们在HNSCC中鉴定出一种新的IFN α诱导的上调lncRNA，lncMX 1 -215。LncMX 1 -215主要定位于细胞核。lncMX 1 -215的异位表达显著抑制IFN α诱导的免疫抑制相关分子程序性细胞死亡1配体1（PD-L1）和半乳糖凝集素-9的表达，反之亦然。随后，组蛋白脱乙酰酶（HDAC）抑制剂促进PD-L1和半乳糖凝集素-9的表达。在PD-L1和半乳糖凝集素-9启动子上发现了H3 K27乙酰化的结合位点。从机制上讲，我们发现lncMX 1 -215直接与GCN 5（一种已知的H3 K27乙酰化酶）相互作用，以中断其与H3 K27乙酰化的结合。临床上，观察到lncMX 1 -215与PD-L1和半乳糖凝集素-9表达之间呈负相关。最后，lncMX 1 -215的过表达在体外和体内抑制HNSCC增殖和转移能力。结论我们的研究结果表明，lncMX 1 -215通过中断HNSCC中GCN 5/H3 K27 ac结合来负调节免疫抑制，从而为免疫检查点阻断治疗提供了新的见解。
Background Interferon alpha (IFN alpha) is a well-established regulator of immunosuppression in head and neck squamous cell carcinoma (HNSCC), while the role of long noncoding RNAs (lncRNAs) in immunosuppression remains largely unknown. Methods Differentially expressed lncRNAs were screened under IFN alpha stimulation using lncRNA sequencing. The role and mechanism of lncRNA in immunosuppression were investigated in HNSCC in vitro and in vivo. Results We identified a novel IFN alpha-induced upregulated lncRNA, lncMX1-215, in HNSCC. LncMX1-215 was primarily located in the cell nucleus. Ectopic expression of lncMX1-215 markedly inhibited expression of the IFN alpha-induced, immunosuppression-related molecules programmed cell death 1 ligand 1 (PD-L1) and galectin-9, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. Binding sites for H3K27 acetylation were found on PD-L1 and galectin-9 promoters. Mechanistically, we found that lncMX1-215 directly interacted with GCN5, a known H3K27 acetylase, to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1-215 and PD-L1 and galectin-9 expression were observed. Finally, overexpression of lncMX1-215 suppressed HNSCC proliferation and metastasis capacity in vitro and in vivo. Conclusions Our results suggest that lncMX1-215 negatively regulates immunosuppression by interrupting GCN5/H3K27ac binding in HNSCC, thus providing novel insights into immune checkpoint blockade treatment.