赖氨酸甲基转移酶 2D (KMT2D) 介导哺乳动物中组蛋白 H3 赖氨酸 4 (H3K4me1) 的单甲基化。 H3K4me1 标记参与建立活性染色质结构以促进基因转录。然而，KMT2D介导的H3K4me1标记调节三阴性乳腺癌（TNBC）进展中基因表达的精确分子机制尚未解决。我们认为Y盒结合蛋白1（YBX1）是H3K4me1标记的“阅读器” ，而 YBX1 (E121A) 的点突变破坏了这种相互作用。我们发现KMT2D和YBX1在体外和体内协同促进TNBC细胞的生长和转移。 KMT2D和YBX1在肿瘤组织中的表达水平均上调，且与乳腺癌患者的不良预后相关。 ChIP-seq 和 RNA-seq 数据的联合分析表明，YBX1 与 KMT2D 介导的 H3K4me1 共定位于 c-Myc 和 SENP1 的启动子区域，从而激活它们在 TNBC 细胞中的表达。此外，我们证明YBX1以KMT2D依赖性方式激活c-Myc和SENP1的表达。我们的结果表明KMT2D介导的H3K4me1招募YBX1通过c-Myc和SENP1的表观遗传激活促进TNBC进展。这些结果共同揭示了 TNBC 进展中组蛋白标记和基因调控之间的关键相互作用，从而为靶向 KMT2D-H3K4me1-YBX1 轴进行 TNBC 治疗提供了新的见解。YBX1 是 KMT2D 介导的 H3K4me1 结合效应蛋白和 YBX1 突变（ E121A) 破坏其与 H3K4me1 的结合。 KMT2D 和 YBX1 通过激活体外和体内 c-Myc 和 SENP1 表达协同促进 TNBC 增殖和转移。在 TNBC 细胞中，YBX1 与 H3K4me1 共定位于 c-Myc 和 SENP1 启动子区域，YBX1 表达增加预示乳腺癌患者预后不良。© 2024 作者。约翰·威利出版的《临床与转化医学》

Lysine methyltransferase 2D (KMT2D) mediates mono-methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D-mediated H3K4me1 mark modulates gene expression in triple-negative breast cancer (TNBC) progression is unresolved.We recognized Y-box-binding protein 1 (YBX1) as a "reader" of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP-seq and RNA-seq data indicated that YBX1 was co-localized with KMT2D-mediated H3K4me1 in the promoter regions of c-Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c-Myc and SENP1 in a KMT2D-dependent manner.Our results suggest that KMT2D-mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c-Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D-H3K4me1-YBX1 axis for TNBC treatment.YBX1 is a KMT2D-mediated H3K4me1-binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c-Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c-Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.