组蛋白H3赖氨酸4三甲基化（H3K4me3）是与活性基因转录相关的经典染色质修饰，对调节多种细胞功能起到关键作用。H3K4me3甲基化酶复合物COMPASS中的非催化组分CXXC型锌指蛋白1（CFP1）在通过逐渐增加的H3K4me3修饰发挥与癌症相关的保护或抑制作用方面已被提及。然而，COMPASS的不可或缺的非催化组分CFP1在恶性进展中的作用仍不明确。我们发现CFP1通过体内外模型促进肺腺癌（LUAD）细胞的增殖、迁移和侵袭，抑制细胞凋亡。此外，高CFP1表达在多个公共和本实验室的LUAD数据集中被证实为不良预后指标。值得注意的是，CFP1缺陷对癌细胞转录组产生双重影响，包括广泛失活癌细胞促进基因和激活癌细胞抑制基因。结合染色质免疫沉淀测序（ChIP-seq）分析，我们展示了CFP1消除对基因组H3K4me3分布特征的重塑，对TGF-β和WNT信号通路产生显著影响。综上所述，我们的研究提出了CFP1通过基因组组蛋白甲基化重编程介导肿瘤发生的观点，为进一步研究癌症进展中的表观遗传修饰以及潜在的治疗进展提供了洞见。© 2023. 四川大学华西医院。

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.© 2023. West China Hospital, Sichuan University.