Histone H1.2 promotes hepatocarcinogenesis by regulating signal transducer and activator of transcription 3 signaling.
Histone H1.2 promotes hepatocarcinogenesis by regulating signal transducer and activator of transcription 3 signaling.
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组蛋白 H1.2 通过调节信号转导子和转录 3 信号激活剂促进肝癌发生
DOI：
10.1111/cas.15336
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发表时间：
2022-05
期刊：
影响因子：
5.7
通讯作者：
Zheng L
中科院分区：
文献类型：
--
作者：
Wang Q;Chen Y;Xie Y;Yang D;Sun Y;Yuan Y;Chen H;Zhang Y;Huang K;Zheng L
连接组蛋白H1.2（H1.2）由HIST1H1C（H1C）编码，是体细胞中一种主要的H1变体。在五种组蛋白H1体细胞变体中，在人类肝细胞癌（HCC）样本以及二乙基亚硝胺（DEN）诱导的HCC小鼠模型中发现H1.2上调。在体外，H1.2过表达加速了HCC细胞系的增殖，而H1.2敲低（KD）则具有相反的效果。在体内，H1.2不足或缺失（H1c KD或H1c KO）减轻了DEN处理小鼠的炎症反应和HCC发展。从机制上讲，H1.2调节信号转导和转录激活因子3（STAT3）的激活，而STAT3反过来通过结合其启动子正向调节H1.2的表达。此外，在人类HCC样本中观察到H1.2/STAT3轴的上调，并且在蛋氨酸 - 胆碱缺乏饮食诱导的非酒精性脂肪性肝炎或脂多糖诱导的急性炎症性肝损伤小鼠模型中得到证实。通过STAT3的KD或用STAT3抑制剂治疗来破坏这种前馈环路，可挽救H1.2过表达诱导的增殖。此外，STAT3抑制剂治疗改善了H1.2过表达促进的异种移植肿瘤生长。因此，H1.2通过调节HCC中STAT3的激活在炎症反应中发挥新的作用，因此，阻断H1.2/STAT3环路是一种针对HCC的潜在策略。
这项研究表明，组蛋白H1.2在肝细胞癌样本中上调，并通过调节信号转导和转录激活因子3（STAT3）的激活促进肝癌发生。STAT3反过来通过结合其启动子上调H1.2，形成一个前馈的H1.2/STAT3环路。H1.2/STAT3环路在炎症性肝损伤模型中进一步得到确认。
Linker histone H1.2 (H1.2), encoded by HIST1H1C (H1C), is a major H1 variant in somatic cells. Among five histone H1 somatic variants, upregulated H1.2 was found in human hepatocellular carcinoma (HCC) samples and in a diethylnitrosamine (DEN)‐induced HCC mouse model. In vitro, H1.2 overexpression accelerated proliferation of HCC cell lines, whereas H1.2 knockdown (KD) had the opposite effect. In vivo, H1.2 insufficiency or deficiency (H1c KD or H1c KO) alleviated inflammatory response and HCC development in DEN‐treated mice. Mechanistically, H1.2 regulated the activation of signal transducer and activator of transcription 3 (STAT3), which in turn positively regulated H1.2 expression by binding to its promoter. Moreover, upregulation of the H1.2/STAT3 axis was observed in human HCC samples, and was confirmed in mouse models of methionine‐choline‐deficient diet induced nonalcoholic steatohepatitis or lipopolysaccharide induced acute inflammatory liver injury. Disrupting this feed‐forward loop by KD of STAT3 or treatment with STAT3 inhibitors rescued H1.2 overexpression‐induced proliferation. Moreover, STAT3 inhibitor treatment‐ameliorated H1.2 overexpression promoted xenograft tumor growth. Therefore, H1.2 plays a novel role in inflammatory response by regulating STAT3 activation in HCC, thus, blockade of the H1.2/STAT3 loop is a potential strategy against HCC. This study showed that histone H1.2 was upregulated in hepatocellular carcinoma samples and promoted hepatocarcinogenesis by regulating signal transducer and activator of transcription 3 (STAT3) activation. STAT3 in turn upregulated H1.2 by binding to its promoter to form a feed‐forward H1.2/STAT3 loop. The H1.2/STAT3 loop was further identified in inflammatory liver injury models.
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影响因子：
9.7
作者：
Pogribny, Igor P.;Rusyn, Ivan
通讯作者：
Rusyn, Ivan
CREBZF 作为 STAT3 通路的关键调节剂控制小鼠肝脏再生
影响因子：
13.5
作者：
Hu, Zhimin;Han, Yamei;Li, Yu
通讯作者：
Li, Yu
影响因子：
5.3
作者：
Fan, YH;Nikitina, T;Skoultchi, AI
通讯作者：
Skoultchi, AI
影响因子：
2.2
作者：
LEENEN, PJM;DEBRUIJN, MFTR;VANEWIJK, W
通讯作者：
VANEWIJK, W
积雪草酸改善 CCl4 诱导的大鼠肝纤维化：涉及 Nrf2/ARE、NF-kappa B/I kappa B α 和 JAK1/STAT3 信号通路
DOI：
10.2147/dddt.s179876
发表时间：
2018
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Fan J;Chen Q;Wei L;Zhou X;Wang R;Zhang H
通讯作者：
Zhang H