Dysregulation of histone acetylation is widely implicated in tumorigenesis, yet its specific roles in the progression and metastasis of esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we profiled the genome-wide landscapes of H3K9ac for paired adjacent normal (Nor), primary ESCC (EC) and metastatic lymph node (LNC) esophageal tissues from three ESCC patients. Compared to H3K27ac, we identified a distinct epigenetic reprogramming specific to H3K9ac in EC and LNC samples relative to Nor samples. This H3K9ac-related reprogramming contributed to the transcriptomic aberration of targeting genes, which were functionally associated with tumorigenesis and metastasis. Notably, genes with gained H3K9ac signals in both primary and metastatic lymph node samples (common-gained gene) were significantly enriched in oncogenes. Single-cell RNA-seq analysis further revealed that the corresponding top 15 common-gained genes preferred to be enriched in mesenchymal cells with high metastatic potential. Additionally, in vitro experiment demonstrated that the removal of H3K9ac from the common-gained gene MSI1 significantly downregulated its transcription, resulting in deficiencies in ESCC cell proliferation and migration. Together, our findings revealed the distinct characteristics of H3K9ac in esophageal squamous cell carcinogenesis and metastasis, and highlighted the potential therapeutic avenue for intervening ESCC through epigenetic modulation via H3K9ac.

组蛋白乙酰化失调广泛参与肿瘤发生，但其在食管鳞状细胞癌（ESCC）进展和转移中的具体作用仍不清楚。在这里，我们分析了来自三名 ESCC 患者的配对相邻正常 (Nor)、原发性 ESCC (EC) 和转移性淋巴结 (LNC) 食管组织的 H3K9ac 全基因组图谱。与 H3K27ac 相比，我们在 EC 和 LNC 样本中（相对于 Nor 样本）发现了 H3K9ac 特有的独特表观遗传重编程。这种与 H3K9ac 相关的重编程导致了目标基因的转录组畸变，而这些基因在功能上与肿瘤发生和转移相关。值得注意的是，在原发性和转移性淋巴结样本中获得 H3K9ac 信号的基因（共同获得基因）在癌基因中显着富集。单细胞RNA-seq分析进一步揭示，相应的前15个常见基因更倾向于富集在具有高转移潜力的间充质细胞中。此外，体外实验表明，从常见基因MSI1中去除H3K9ac会显着下调其转录，导致ESCC细胞增殖和迁移缺陷。总之，我们的研究结果揭示了 H3K9ac 在食管鳞状细胞癌发生和转移中的独特特征，并强调了通过 H3K9ac 表观遗传调节干预 ESCC 的潜在治疗途径。