组蛋白脱乙酰酶 (HDAC) 是基因表达、DNA 合成和细胞过程的重要调节因子，使其成为癌症研究的重要靶点。具体来说，HDAC6 会影响蛋白质稳定性和染色质动力学。尽管 HDAC6 具有潜在的治疗价值，但其在基因调控和染色质重塑中的确切作用需要进一步阐明。本研究探讨了 HDAC6 失活如何影响赖氨酸乙酰转移酶 P300 的稳定性以及随后对癌细胞染色质结构和功能的影响。我们采用 HDAC6 抑制剂 ITF3756、siRNA 或 CRISPR/Cas9 基因编辑在不同的表观基因组背景下失活 HDAC6。这种失活不断导致染色质可及性发生显着变化，特别是组蛋白 H3 赖氨酸 9、14 和 27 的乙酰化增加（ATAC-seq 和 H3K27Ac ChIP-seq 分析）。转录组学、蛋白质组学和基因本体分析揭示了细胞增殖、粘附、迁移和凋亡中的基因变化。值得注意的是，HDAC6 失活改变了 P300 泛素化，稳定了 P300 并导致对癌细胞生存至关重要的基因下调。我们的研究强调了 HDAC6 失活对癌细胞染色质景观的重大影响，并表明 P300 在抗癌作用中发挥着重要作用。 HDAC6 抑制使 P300 稳定，这表明治疗重点可能从 HDAC6 本身转移到其与 P300 的相互作用。这一发现为开发靶向癌症疗法开辟了新途径，提高了我们对癌细胞表观遗传机制的理解。© 2024。作者。

Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells.We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival.Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.© 2024. The Author(s).