The modulation of PD-L1 induced by the oncogenic HBXIP for breast cancer growth
The modulation of PD-L1 induced by the oncogenic HBXIP for breast cancer growth
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致癌 HBXIP 诱导的 PD-L1 对乳腺癌生长的调节
DOI：
10.1038/s41401-021-00631-6
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发表时间：
2021-04-06
影响因子：
8.2
通讯作者：
Ye, Li-hong
中科院分区：
文献类型：
--
作者：
Xu, Fei-fei;Sun, Hui-min;Ye, Li-hong
程序性死亡配体-1（PD-L1）/PD-1检查点广泛用作免疫抑制的中心介质。揭示了在几种癌症中丰富的PD-L1的肿瘤促进作用。然而，PD-L1的重要性以及PD-L1表达在乳腺癌中的控制方式仍然不清楚。在此，介绍了在转录和蛋白乙酰化水平上控制PD-L1促进乳腺癌生长的机制。过表达的PD-L1在体外和体内加速乳腺癌生长。RNA-seq发现PD-L1可以诱导一些靶基因，影响许多细胞过程，特别是癌症的发展。在临床乳腺癌组织和细胞中，PD-L1和HBXIP均增高，且两者表达呈正相关。机制探索确定HBXIP通过共激活ETS2刺激PD-L1的转录。具体而言，HBXIP通过与乙酰转移酶p300相互作用诱导PD-L1在K270位点的乙酰化，从而导致PD-L1蛋白的稳定性。在功能上，HBXIP的消耗减弱了PD-L1加速的乳腺肿瘤生长。阿司匹林通过靶向PD-L1和HBXIP治疗乳腺癌。总的来说，这些发现为控制肿瘤PD-L1的机制提供了新的线索，并拓宽了PD-L1作为乳腺癌治疗靶点的实用性。
Programmed death ligand-1 (PD-L1)/PD-1 checkpoint extensively serves as a central mediator of immunosuppression. A tumor-promoting role for abundant PD-L1 in several cancers is revealed. However, the importance of PD-L1 and how the PD-L1 expression is controlled in breast cancer remains obscure. Here, the mechanisms of controlling PD-L1 at the transcription and protein acetylation levels in promoting breast cancer growth are presented. Overexpressed PD-L1 accelerates breast cancer growth in vitro and in vivo. RNA-seq uncovers that PD-L1 can induce some target genes affecting many cellular processes, especially cancer development. In clinical breast cancer tissues and cells, PD-L1 and HBXIP are both increased, and their expressions are positively correlated. Mechanistic exploration identifies that HBXIP stimulates the transcription of PD-L1 through co-activating ETS2. Specifically, HBXIP induces PD-L1 acetylation at K270 site through interacting with acetyltransferase p300, leading to the stability of PD-L1 protein. Functionally, depletion of HBXIP attenuates PD-L1-accelerated breast tumor growth. Aspirin alleviates breast cancer via targeting PD-L1 and HBXIP. Collectively, the findings display new light into the mechanisms of controlling tumor PD-L1 and broaden the utility for PD-L1 as a target in breast cancer therapy.