PD-L1
癌症研究
免疫系统
转录因子
增强子
IRF8
生物
癌细胞
组蛋白
免疫检查点
化学
癌症
免疫疗法
分子生物学
免疫学
基因
生物化学
遗传学
作者
Wei Xiong,Huanghao Deng,Chí Huang,Chong Zen,Chengzhu Jian,Kun Ye,Zhaohui Zhong,Xiaokun Zhao,Liang Zhu
标识
DOI:10.1016/j.bbadis.2018.10.027
摘要
Tumor cells utilize the overexpression of the programmed death-1 ligand 1(PD-L1) to escape T-cell controlled immune-surveillance. The clinical therapy that dilapidates PD1 or PD-L1-mediated cancer tolerance has pushed out the need to uncover the molecular regulation of PD-L1 overexpression in the tumor cell. In this study, we identify histone methyltransferase mixed-lineage leukemia protein 3 (MLL3) as a critical regulator of PD-L1 in prostate cancer cells. MLL3 and PD-L1 were highly expressed in the metastatic cancer tissues, compared to the primary cancer tissues. Furthermore, their expressions were highly correlated in the cancer tissues in the databases of TCGA and Xiangya Hospital. We found that MLL3 bound to the enhancer of PD-L1. Depletion of MLL3 decreased the binding level of H3K4me1 in the enhancer of PD-L1 and Pol II Ser-5p in the promoter of PD-L1. Importantly, MLL3 depletion impaired the mouse xenograft growth and decreased the response to PD-L1 antibody treatment in mice. The findings extend the understanding of the biology regulation of PD-L1 transcription and identify the histone writer MLL3 in an important immune checkpoint, and give prominence to a hidden therapeutic target to conquer immune evasion by tumor cells.
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