肝细胞癌（HCC）是一个重大的全球健康挑战。自噬的激活对于促进癌细胞的增殖和存活起着至关重要的作用。然而，肝癌中自噬的上游调控网络和机制仍不清楚。这项研究表明组蛋白脱乙酰酶 2 (HDAC2) 调节 HCC 中的自噬。 HDAC2 的表达在 HCC 组织中升高，并且 HDAC2 的高表达与 HCC 个体的不良预后密切相关。体外和体内综合研究证实，HDAC2 促进 HCC 中的自噬和自噬相关的恶性进展。从机制上讲，HDAC2 在四个不同的结合位点与溶酶体相关蛋白跨膜 4-β (LAPTM4B) 启动子特异性结合，增强其转录激活并驱动 HCC 中自噬相关的恶性进展。这些发现确定 LAPTM4B 是 HDAC2 的直接靶基因。此外，HDAC2的选择性抑制剂有效缓解HCC的恶性发展。此外，对 105 个人类 HCC 样本的多变量 Cox 回归分析表明，HDAC2 表达是 HCC 预后的独立预测因子。这项研究强调了 HDAC2-LAPTM4B 轴在调节 HCC 恶性进化中自噬的关键作用，并强调了靶向 HDAC2 预防和阻止 HCC 恶性进展的潜力。© 2024。作者。

Hepatocellular carcinoma (HCC) is a significant global health challenge. The activation of autophagy plays an essential role in promoting the proliferation and survival of cancer cells. However, the upstream regulatory network and mechanisms governing autophagy in HCC remain unclear. This study demonstrated that histone deacetylase 2 (HDAC2) regulates autophagy in HCC. Its expression was elevated in HCC tissues, and high HDAC2 expression was strongly associated with poor prognosis in individuals with HCC. Integrated in vitro and in vivo investigations confirmed that HDAC2 promotes autophagy and autophagy-related malignant progression in HCC. Mechanistically, HDAC2 bound specifically to the lysosome-associated protein transmembrane 4-β (LAPTM4B) promoter at four distinct binding sites, enhancing its transcriptional activation and driving autophagy-related malignant progression in HCC. These findings establish LAPTM4B as a direct target gene of HDAC2. Furthermore, the selective inhibitor of HDAC2 effectively alleviated the malignant development of HCC. In addition, multivariate Cox regression analysis of 105 human HCC samples revealed that HDAC2 expression is an independent predictor of HCC prognosis. This study underscores the crucial role of the HDAC2-LAPTM4B axis in regulating autophagy in the malignant evolution of HCC and highlights the potential of targeting HDAC2 to prevent and halt the malignant progression of HCC.© 2024. The Author(s).