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.