Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Signal Transduct Target Ther. 2023 Sep 21;8(1):369. doi: 10.1038/s41392-023-01612-3.
Histone H3 lysine 4 trimethylation (H3K4me3) is a canonical chromatin modification associated with active gene transcription, playing a pivotal role in regulating various cellular functions. Components of the H3K4me3 methyltransferase complex, known as the proteins associated with SET1 (COMPASS), have been implicated in exerting cancer-protective or cancer-inhibitory effects through inducive H3K4me3 modification. However, the role of the indispensable non-catalytic component of COMPASS CXXC-type zinc finger protein 1 (CFP1) in malignant progression remains unclear. We have unveiled that CFP1 promote lung adenocarcinoma (LUAD) cell proliferation, migration, and invasion while impairing cell apoptosis through in vitro and in vivo models. In addition, high CFP1 expression was identified as emerged as an adverse prognostic indicator across multiple public and in-house LUAD datasets. Notably, CFP1 deficiency led to dual effects on cancer cell transcriptome including extensive inactivation of cancer-promoting as well as activation of cancer repressors. Combining this with the chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we showed that CFP1 ablation reshaped the genomic H3K4me3 distribution signature, with prominent effects on TGF-β and WNT signaling pathways. Collectively, our study proposes that CFP1 mediates tumorigenesis by genomic histone methylation reprogramming, offering insights for future investigations into epigenetic modifications in cancer progression and potential therapeutic advancements.
组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3）是一种与活跃基因转录相关的典型染色质修饰，在调节各种细胞功能中起着关键作用。H3K4me3 甲基转移酶复合物的组成部分，即与 SET1（COMPASS）相关的蛋白质，已被证明通过诱导 H3K4me3 修饰发挥抗癌或抑癌作用。然而，COMPASS 的不可或缺的非催化成分CXXC 型锌指蛋白 1（CFP1）在恶性进展中的作用仍不清楚。我们通过体外和体内模型揭示，CFP1 通过促进肺腺癌（LUAD）细胞增殖、迁移和侵袭，同时损害细胞凋亡，从而促进 LUAD 进展。此外，高 CFP1 表达被确定为多个公共和内部 LUAD 数据集的不良预后指标。值得注意的是，CFP1 缺失对癌细胞转录组具有双重影响，包括广泛失活致癌基因和激活抑癌基因。结合染色质免疫沉淀测序（ChIP-seq）分析，我们表明 CFP1 缺失重塑了基因组 H3K4me3 分布特征，对 TGF-β 和 WNT 信号通路有显著影响。综上所述，我们的研究表明 CFP1 通过基因组组蛋白甲基化重编程介导肿瘤发生，为癌症进展中的表观遗传修饰和潜在的治疗进展提供了新的研究视角。
