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赖氨酰氧化酶LOXL4去组蛋白H4K8乙酰化促进结直肠癌进展的分子机制研究

项目来源

国家自然科学基金(NSFC)

项目主持人

吴孟

项目受资助机构

苏州大学

立项年度

2018

立项时间

未公开

项目编号

31801058

研究期限

未知 / 未知

项目级别

国家级

受资助金额

26.00万元

学科

生命科学-遗传学与生物信息学-遗传物质结构与功能

学科代码

C-C06-C0601

基金类别

青年科学基金项目

关键词

LOXL4 ; 人类 ; 组蛋白去修饰酶 ; 结直肠癌 ; H4K8乙酰化 ; LOXL4 ; 人类 ; 组蛋白去修饰酶 ; 结直肠癌 ; H4K8乙酰化

参与者

张亚楠；黄仁鹏；徐蒙蒙；李相融；郑梦歌；胡昌勇

参与机构

苏州大学；同济大学

项目标书摘要：表观遗传变异在结直肠癌发生发展中起重要作用。赖氨酰氧化酶LOXL4在结直肠癌中高表达，预示了其潜在的促癌功能。我们预实验发现，过表达LOXL4可特异降低组蛋白H4K8乙酰化并能促进结肠癌细胞增殖、侵袭和迁移；纯化的LOXL4可在体外去除H4K8乙酰化。据此我们提出假说:LOXL4是一个新的组蛋白去乙酰化酶，通过去除H4K8乙酰化调控基因表达，促进结肠癌进展。围绕这一假说，我们将用蛋白质谱技术、基因组学高通量分析及小鼠移植瘤模型等手段1研究LOXL4催化H4K8去乙酰化的作用机理;2鉴定LOXL4的靶基因;3阐明LOXL4作为组蛋白去乙酰化酶调控靶基因表达促进结直肠癌进展的分子机制。本项目的顺利实施将揭示LOXL4的去乙酰化酶活性，发现结直肠癌治疗的新靶点，并为针对结直肠癌靶向治疗的药物研发提供理论依据。

Application Abstract: Epigenetic aberrations are frequent events in colorectal cancer(CRC).Lysyl oxidase like 4(LOXL4)has been reported to be overexpressed in CRC,which might underlies its oncogenic potential.Our preliminary data showed that,histone H4K8 acetylation was markedly reduced when LOXL4 was ectopically expressed in HEK293T cells.In vitro histone H4K8 deacetylation was also observed by incubating affinity-purified LOXL4 and core histones.Furthermore,in HCT116 colorectal cancer cell line,overexpression of LOXL4 significantly increased cell proliferation,migration and invasion.Therefore,we propose that,LOXL4 is a novel histone deacetylase that accelerates colorectal cancer progression by deacetylating histone H4K8.Utilizing mass spectrometry technique,large-scale genomic analysis and mouse xenograft model,this project will further 1)decipher the mechanism of LOXL4 catalyzed deacetylation of H4K8;2)identify LOXL4 target genes;3)determine the mechanism of LOXL4 in promoting colorectal cancer progression by removing histone H4K8 acetylation.The proposed study would potentially lead to identify a novel histone deacetylase and reveal a new drug target in colorectal cancer.

项目受资助省

江苏省

项目结题报告(全文)

LOXL4(Lysyl oxidases like 4)是赖氨酰氧化酶(Lysyl oxidases,LOX)家族成员，研究发现该家族蛋白是一类铜离子依赖的分泌型赖氨酰氧化酶，通过催化弹性纤维蛋白和胶原蛋白赖氨酰氧化反应使之相互交联，参与调节细胞外基质的稳态。近年有研究揭示LOX家族在肿瘤的增殖、侵袭和迁移过程中发挥重要作用,LOXL4在结直肠癌中发挥的作用尚不明确。组蛋白修饰是表观遗传调控的重要方面，并且与结直肠癌发生发展密切相关，结直肠癌细胞系和肿瘤组织中总体组蛋白H3和H4乙酰化水平明显下降，多个组蛋白去乙酰化酶抑制剂作为结直肠癌靶向治疗药物正处于临床前或临床研究阶段，组蛋白去乙酰化酶也被认为是有希望的结直肠癌治疗靶点。本项目利用TCGA(The Cancer Genom Eatlas)和GEO(Gene Expression Omnibus)数据库分析，发现相比癌旁组织结直肠癌病人肿瘤组织中的LOXL4的表达水平更高，且LOXL4表达更高的结直肠癌患者的预后更差。利用构建过表达或者敲除LOXL4的结直肠癌细胞系进行的CCK8细胞增殖实验和Trans-Well以及裸鼠移植瘤模型等实验分别在细胞水平和动物水平上发现LOXL4会促进结直肠癌的发生发展。在我们通过免疫印迹和Orbitrap LC-MS等技术发现LOXL4可以特异性去除组蛋白H4八号赖氨酸(H4K8)上的乙酰基团。RNA-Seq和ChIP(染色质免疫共沉淀)-Seq发现LOXL4通过影响组蛋白H4K8的乙酰化水平从而调控WNT/β-catenin通路相关基因的转录。本研究首次鉴定出LOXL4是组蛋白H4K8的特异性去乙酰化酶，通过去乙酰化组蛋白H4K8调控WNT/β-catenin通路相关基因的转录促进结直肠癌增殖、迁移和侵袭的分子机制，有望为找寻结直肠癌预防和治疗新的生物标志物提供新思路。此外，在本项目资助下，我们还发现赖氨酸甲基转移酶EZH2能够发生N-豆蔻酰化修饰，并阐明豆蔻酰化通过介导疏水相互作用驱动EZH2发生液—液相分离，招募并活化STAT3,促进肺癌恶性进展的分子机制。为肺癌的精准治疗提供新靶点，为靶向EZH2的药物开发提供新视角。

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  • 1.Myristoylation-mediated phase separation of EZH2 compartmentalizes STAT3 to promote lung cancer growth

    • 《CANCER LETTERS》
    • 2021年
    • 516卷
    • 期刊

    N-myristoylation is a crucial signaling and pathogenic modification process that confers hydrophobicity to cytosolic proteins. Although different large-scale approaches have been applied, a large proportion of myristoylated proteins remain to be identified. EZH2 is overexpressed in lung cancer cells and exerts oncogenic effects via its intrinsic methyltransferase activity. Using a well-established click chemistry approach, we found that EZH2 can be modified by myristoylation at its N-terminal glycine in lung cancer cells. Hydrophobic interaction is one of the main forces driving or stabilizing liquid-liquid phase separation (LLPS), raising the possibility that myristoylation can modulate LLPS by mediating hydrophobic interactions. Indeed, myristoylation facilitates EZH2 to form phase-separated liquid droplets in lung cancer cells and in vitro. Furthermore, we provide evidence that myristoylation-mediated LLPS of EZH2 compartmentalizes its non-canonical substrate, STAT3, and activates STAT3 signaling, ultimately resulting in accelerated lung cancer cell growth. Thus, targeting EZH2 myristoylation may have significant therapeutic efficacy in the treatment of lung cancer. Altogether, these observations not only extend the list of myristoylated proteins, but also indicate that hydrophobic lipidation may serve as a novel incentive to induce or maintain LLPS.

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