HDAC2通过转录激活LAPTM4B促进与自噬相关的HCC恶性进展
HDAC2 promotes autophagy-associated HCC malignant progression by transcriptionally activating LAPTM4B
影响因子:9.60000
分区:生物学1区 Top / 细胞生物学2区
发表日期:2024 Aug 15
作者:
Meifeng Wang, Jianping Liao, Jie Wang, Meifang Xu, Ye Cheng, Lixin Wei, Aimin Huang
摘要
肝细胞癌（HCC）是一项重大的全球健康挑战。自噬的激活在促进癌细胞的增殖和存活中起着至关重要的作用。但是，尚不清楚hCC自噬的上游监管网络和管理自噬的机制。这项研究表明，组蛋白脱乙酰基酶2（HDAC2）调节HCC中的自噬。它的表达在HCC组织中升高，高HDAC2表达与HCC患者的预后不良密切相关。在体外和体内研究中进行了整合，证实HDAC2促进了HCC中的自噬和自噬相关的恶性肿瘤。从机械上讲，HDAC2在四个不同的结合位点上专门与溶酶体相关蛋白跨膜4-β（LAPTM4B）启动子结合，增强了其转录激活并驱动了HCC中与自噬相关的恶性肿瘤。这些发现将LAPTM4B作为HDAC2的直接靶基因。此外，HDAC2的选择性抑制剂有效缓解了HCC的恶性发展。此外，对105人HCC样品的多元COX回归分析表明，HDAC2表达是HCC预后的独立预测指标。这项研究强调了HDAC2-LAPTM4B轴在HCC的恶性进化中调节自噬的关键作用，并突出了靶向HDAC2预防和停止HCC的恶性进展的潜力。
Abstract
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.