一种新型 IFNα 诱导的长非编码 RNA 通过中断头颈部鳞状细胞癌中的 H3K27 乙酰化来负调控免疫抑制。
A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma.
机构信息
Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China.
National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.
出版信息
Mol Cancer. 2020 Jan 6;19(1):4. doi: 10.1186/s12943-019-1123-y.
BACKGROUND
Interferon alpha (IFNα) 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 IFNα 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 IFNα-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 IFNα-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.
背景
干扰素 alpha（IFNα）是头颈部鳞状细胞癌（HNSCC）中免疫抑制的一种成熟调节剂，而长链非编码 RNA（lncRNA）在免疫抑制中的作用在很大程度上尚不清楚。
方法
使用 lncRNA 测序在 IFNα 刺激下筛选差异表达的 lncRNA。在体外和体内研究 lncRNA 在 HNSCC 免疫抑制中的作用和机制。
结果
我们在 HNSCC 中鉴定了一种新型 IFNα诱导上调的 lncRNA，lncMX1-215。lncMX1-215 主要位于细胞核内。lncMX1-215 的异位表达显著抑制了 IFNα诱导的免疫抑制相关分子程序性细胞死亡配体 1（PD-L1）和半乳糖凝集素-9 的表达，反之亦然。随后，组蛋白去乙酰化酶（HDAC）抑制剂促进了 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 H3K27 乙酰化的结合位点。从机制上讲，我们发现 lncMX1-215 直接与 GCN5（一种已知的 H3K27 乙酰转移酶）相互作用，从而阻止其与 H3K27 乙酰化结合。临床上，观察到 lncMX1-215 与 PD-L1 和半乳糖凝集素-9 表达呈负相关。最后，lncMX1-215 的过表达抑制了体外和体内 HNSCC 的增殖和转移能力。
结论
我们的研究结果表明，lncMX1-215 通过中断 GCN5/H3K27ac 在 HNSCC 中的结合，负调控免疫抑制，从而为免疫检查点阻断治疗提供了新的见解。
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