Peripheral T cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Here, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing MNU-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Key words: Histone deacetylases (HDACs), Natural killer (NK) cells, Peripheral T cell lymphoma (PTCL)

中文翻译：

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HDAC 抑制增加 CXCL12 分泌以招募外周 T 细胞淋巴瘤中的自然杀伤细胞

外周T细胞淋巴瘤（PTCL）是一种异质性、侵袭性疾病，预后不良。组蛋白脱乙酰酶 (HDAC) 抑制剂已显示出对 PTCL 的抑制作用。更好地了解 HDAC 抑制剂作用的治疗机制可能有助于改进治疗策略。在这里，我们发现 HDAC3 的高表达与 PTCL 的不良预后相关。 HDAC3 抑制可抑制免疫功能正常小鼠的淋巴瘤生长，但不能抑制免疫缺陷小鼠的淋巴瘤生长。 HDAC3 缺失延缓了淋巴瘤的进展，减少了胸腺、脾脏和淋巴结的淋巴瘤负担，并延长了患有 MNU 诱导淋巴瘤的小鼠的生存期。此外，抑制 HDAC3 可促进自然杀伤 (NK) 细胞的浸润并增强其功能。从机制上讲，HDAC3 介导 ATF3 脱乙酰化，增强其转录抑制活性。靶向 HDAC3 通过 ATF3 依赖性途径增强 CXCL12 分泌，刺激 NK 细胞招募和激活。最后，HDAC3 抑制改善了 PTCL 对常规化疗的反应。总的来说，这项研究深入了解了 HDAC3 调节 ATF3 活性和 CXCL12 分泌，从而导致免疫浸润和淋巴瘤抑制的机制。 HDAC3 抑制剂与化疗相结合可能是治疗 PTCL 的一种有前景的策略。关键词: 组蛋白脱乙酰酶 (HDAC), 自然杀伤 (NK) 细胞, 外周 T 细胞淋巴瘤 (PTCL)