O-GlcNAcylation of histone deacetylase-1 in hepatocellular carcinoma promotes cancer progression
O-GlcNAcylation of histone deacetylase-1 in hepatocellular carcinoma promotes cancer progression
复制标题
肝细胞癌中组蛋白脱乙酰酶 1 的 O-GlcNAc 酰化促进癌症进展
DOI：
10.1093/glycob/cww025
复制
发表时间：
2016
期刊：
影响因子：
4.3
通讯作者：
Shen Aiguo
中科院分区：
文献类型：
--
作者：
Zhu Guizhou;Tao Tao;Zhang Dongmei;Liu Xiaojuan;Qiu Huiyuan;Han LiJian;Xu Zhiwei;Xiao Ying;Cheng Chun;Shen Aiguo
肝细胞癌（HCC）是一种起源于肝脏的恶性肿瘤。以往的研究表明，O-GlcNAc转移酶（OGT）和组蛋白去乙酰化酶-1（HDAC 1）在肝癌的发病机制中起重要作用。在本研究中，我们研究了OGT和HDAC 1之间的物理联系。HDAC 1的O-GlcNAc化在HCC中过表达。我们发现HDAC 1在其组蛋白去乙酰化酶结构域中有两个主要的O-GlcNAc化位点。HDAC 1 O-GlcNAc化增加HDAC 1的活化磷酸化，这增强其酶活性。HDAC 1 O-GlcNAc突变体通过影响染色体组蛋白乙酰化水平，促进p21转录调控，进而影响肝癌细胞增殖。我们还发现HDAC 1的O-GlcNAc化位点突变影响HepG 2细胞的侵袭和迁移。HDAC 1 O-GlcNAc突变体处理肝癌细胞后，E-cadherin水平显著上调，抑制了肝癌的发生和发展。我们的研究结果表明，OGT促进HDAC 1的O-GlcNAc修饰在肝癌的发展。因此，抑制HDAC 1的O-GlcNAc化可能抑制HCC的进展。
Hepatocellular carcinoma (HCC) is a malignant tumor originating in the liver. Previous studies have indicated that O-GlcNAc transferase (OGT) and histone deacetylase-1 (HDAC1) play important roles in the pathogenesis of HCC. In the present study, we investigated the physical link between OGT and HDAC1. The O-GlcNAcylation of HDAC1 is overexpressed in HCC. We found that HDAC1 has two major sites of O-GlcNAcylation in its histone deacetylase domain. HDAC1 O-GlcNAcylation increases the activated phosphorylation of HDAC1, which enhances its enzyme activity. HDAC1 O-GlcNAc mutants promote the p21 transcription regulation through affecting the acetylation levels of histones from chromosome, and then influence the proliferation of HCC cells. We also found that mutants of O-GlcNAcylation site of HDAC1 affect invasion and migration of HepG2 cells. E-cadherin level is highly up-regulated in HDAC1 O-GlcNAc mutant-treated liver cancer cells, which inhibit the occurrence and development of HCC. Our findings suggest that OGT promotes the O-GlcNAc modification of HDAC1in the development of HCC. Therefore, inhibiting O-GlcNAcylation of HDAC1 may repress the progression of HCC.