Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing 100191, China.
Breast Disease Center, Peking University People's Hospital, Beijing 100044, China.
Cell Rep. 2023 Nov 28;42(11):113343. doi: 10.1016/j.celrep.2023.113343. Epub 2023 Oct 31.
The intrinsic regulation of programmed death ligand-1 (PD-L1) expression remains unclear. Here, we report that zinc-finger protein 652 (ZNF652) is a potent transcription repressor of PD-L1. ZNF652 frequently experiences loss of heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription co-repressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and a low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8 T cells, and poor prognosis in TNBC. Our study provides insights into PD-L1 regulation and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.
程序性死亡配体 1（PD-L1）表达的内在调控机制尚不清楚。在这里，我们报告锌指蛋白 652（ZNF652）是 PD-L1 的一个强有力的转录抑制因子。ZNF652 在各种癌症中经常经历杂合性丢失（LOH）。较高的 LOH 率和缺乏雌激素诱导的转录导致三阴性乳腺癌（TNBC）中 ZNF652 的表达受到抑制。在机制上，ZNF652 与 NuRD 转录共抑制复合物物理相关，以抑制包括 PD-L1 在内的一组基因。ZNF652 的过表达抑制 PD-L1 的转录，而 ZNF652 的耗竭则上调 PD-L1。在 TNBC 中缺失 ZNF652 会在体外和体内释放 PD-L1 介导的免疫逃逸。重要的是，ZNF652 的表达在乳腺癌进展过程中逐渐丢失，低水平的 ZNF652 与 PD-L1 表达升高、CD8 T 细胞浸润减少和 TNBC 预后不良相关。我们的研究为 PD-L1 的调控提供了新的见解，并支持将 ZNF652 作为乳腺癌免疫治疗的潜在生物标志物和药物靶点进行研究。
