Abstract
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.
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Data availability
The ChIP-seq data generated in this study have been deposited in GEO (GSE234346).
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Funding
This work was supported by the National Key Research and Development Program of China (2021YFC2501005), the National Natural Science Foundation of China (82172882), the Zhejiang Provincial Natural Science Foundation of China (LQ23H160051 and LTGY23H180010).
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JS, ZC, and YY conceived and designed the study. YQ and GC contributed to the acquisition of samples and clinical data. ZC and YZ performed the ChIP-seq and in vitro functional experiments. CL and PL performed the bioinformatic analysis. ZC, CL, YY, and JS wrote the manuscripts. All authors reviewed and approved the final manuscript.
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Chen, Z., Li, C., Zhou, Y. et al. Histone 3 lysine 9 acetylation-specific reprogramming regulates esophageal squamous cell carcinoma progression and metastasis. Cancer Gene Ther 31, 612–626 (2024). https://doi.org/10.1038/s41417-024-00738-y
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DOI: https://doi.org/10.1038/s41417-024-00738-y