TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma.
TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma.
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DOI：
10.1111/cas.14897
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发表时间：
2021-07
期刊：
影响因子：
5.7
通讯作者：
Aburatani H
中科院分区：
文献类型：
--
作者：
Shirai K;Nagae G;Seki M;Kudo Y;Kamio A;Hayashi A;Okabe A;Ota S;Tsutsumi S;Fujita T;Yamamoto S;Nakaki R;Kanki Y;Osawa T;Midorikawa Y;Tateishi K;Ichinose M;Aburatani H
TET 1（英语：Ten‐eleven translocation 1）是DNA去甲基化途径中的一种重要的甲基胞嘧啶双加氧酶。尽管已知TET 1在人类癌症中发生失调，但其作用仍然知之甚少。在这项研究中，我们报告TET 1促进人类肝癌细胞生长。对68份临床肝脏样本的转录组分析显示了TET 1上调的肝细胞癌（HCC）亚组，证明了成肝细胞样基因表达特征。我们进行了全面的胞嘧啶甲基化和羟甲基化（5-hmC）分析，发现5-hmC异常地优先沉积在活性增强子中。肝癌细胞系中TET 1的敲低降低了hmC沉积，并抑制了细胞生长。HMGA 2在HCC的TET 1high亚组中高度表达，与其内含子区域的超羟甲基化相关，标记为组蛋白H3 K4-单甲基化，其中H3 K27-乙酰化的活性增强子染色质状态诱导与其启动子的相互作用。总的来说，我们的研究结果指出了一种新型的表观遗传失调，甲基胞嘧啶双加氧酶TET 1，它通过其致癌靶点HMGA 2的异位增强子促进成肝细胞样HCC中的细胞增殖。10 - 11易位1（TET 1）是DNA去甲基化途径的甲基胞嘧啶双加氧酶，在肝细胞癌亚组中过表达，具有成肝细胞样表达模式。全面的表观基因组分析显示，HMGA 2通过胞嘧啶羟甲基化、H3 K27乙酰化、H3 K4单甲基化和启动子-增强子相互作用以TET 1依赖性方式异位激活增强子。
Ten‐eleven translocation 1 (TET1) is an essential methylcytosine dioxygenase of the DNA demethylation pathway. Despite its dysregulation being known to occur in human cancer, the role of TET1 remains poorly understood. In this study, we report that TET1 promotes cell growth in human liver cancer. The transcriptome analysis of 68 clinical liver samples revealed a subgroup of TET1‐upregulated hepatocellular carcinoma (HCC), demonstrating hepatoblast‐like gene expression signatures. We performed comprehensive cytosine methylation and hydroxymethylation (5‐hmC) profiling and found that 5‐hmC was aberrantly deposited preferentially in active enhancers. TET1 knockdown in hepatoma cell lines decreased hmC deposition with cell growth suppression. HMGA2 was highly expressed in a TET1high subgroup of HCC, associated with the hyperhydroxymethylation of its intronic region, marked as histone H3K4–monomethylated, where the H3K27‐acetylated active enhancer chromatin state induced interactions with its promoter. Collectively, our findings point to a novel type of epigenetic dysregulation, methylcytosine dioxygenase TET1, which promotes cell proliferation via the ectopic enhancer of its oncogenic targets, HMGA2, in hepatoblast‐like HCC. Ten‐eleven translocation 1 (TET1), a methylcytosine dioxygenase of the DNA demethylation pathway, is overexpressed in the subgroup of hepatocellular carcinoma with the hepatoblast‐like expression pattern. Comprehensive epigenome profilings revealed the ectopic enhancer activation of HMGA2 through cytosine hydroxymethylation, H3K27 acetylation, H3K4 monomethylation, and promoter‐enhancer interaction in a TET1‐dependent manner.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I
影响因子：
11.2
作者：
Filipczak, Piotr T.;Leng, Shuguang;Belinsky, Steven A.
通讯作者：
Belinsky, Steven A.
影响因子：
11.2
作者：
Good CR;Panjarian S;Kelly AD;Madzo J;Patel B;Jelinek J;Issa JJ
通讯作者：
Issa JJ