HDAC2通过转录激活LAPTM4B促进自噬相关的肝细胞癌恶性进展
HDAC2 promotes autophagy-associated HCC malignant progression by transcriptionally activating LAPTM4B
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影响因子:9.6
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
DOI:
10.1038/s41419-024-06981-3
摘要
肝细胞癌（HCC）是全球重要的公共卫生挑战。自噬的激活在促进癌细胞增殖和存活中起着关键作用。然而，调控HCC中自噬的上游调控网络和机制尚不清楚。本研究显示组蛋白去乙酰酶2（HDAC2）调控HCC中的自噬，其在HCC组织中的表达升高，且高HDAC2表达与HCC患者预后不良密切相关。体外和体内的联合研究证实，HDAC2促进HCC中的自噬以及相关的恶性进展。从机制上讲，HDAC2在四个不同的结合位点特异性结合到溶酶体相关蛋白跨膜4-β（LAPTM4B）启动子上，增强其转录激活，推动HCC中的自噬相关恶性进展。这些发现确立了LAPTM4B作为HDAC2的直接靶基因。此外，选择性HDAC2抑制剂有效缓解了HCC的恶性发展。此外，对105个人类HCC样本的多变量Cox回归分析显示，HDAC2表达是HCC预后的独立预测因子。本研究强调了HDAC2-LAPTM4B轴在调控HCC恶性演变中自噬的重要作用，并突出显示了靶向HDAC2以预防和阻止HCC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.