靶向治疗染色质重塑因子ARID1A突变肿瘤的分子机理

染色质重塑因子ARID1A(the AT-rich interaction domain 1A)基因是肿瘤中突变率最高的基因之一,ARID1A突变通常导致其蛋白质表达和功能缺失,ARID1A突变的肿瘤细胞和小鼠模型均证明ARID1A突变可促进肿瘤发生发展,提示ARID1A突变在肿瘤演化中的恶性作用。挖掘靶向ARID1A突变肿瘤细胞的治疗方式和药物靶标有助于未来靶向ARID1A突变肿瘤的临床药物研发,且具有临床应用意义。该文总结了针对ARID1A突变肿瘤细胞的合成致死(synthetic lethality)方法和ARID1A突变肿瘤免疫治疗策略的分子机理和最新研究进展,旨在为未来探索ARID1A突变肿瘤的临床治疗方法提供参考。     

抑癌基因ARID1A在肿瘤中的研究进展

染色质重塑复合物相关基因在癌症中频繁突变,这种现象逐渐引起研究者的重视。然而,染色质重塑活动如何引起癌症发生,对此机理研究甚少。ARID1A是SWl／SNF（BRG1相关因子）染色质重塑复合物中的一个亚基,具有DNA结合活性,可以与富含AT的DNA序列特异性结合。近来基因组测序发现,ARID1A在卵巢癌、肝癌、胃癌、乳腺癌等肿瘤中频繁发生突变,这些突变导致ARID1A在肿瘤中表达降低,表明ARID1A是个潜在的抑癌基因。该文将针对ARID1A在各种癌症中的缺失及失活机制、ARID1A的生物学功能和潜在抑癌机理以及与,临床预后之间关系等方面做一综述,以期为肿瘤诊断、治疗提供新思路。     

染色质重塑因子在植物发育过程的功能

染色质重塑复合体(chromatin remodeling complexes)通过具有ATPase活性的亚基水解ATP释放能量,通过改变核小体"构象"(包括核小体重定位、核小体滑动和核小体替换等)而改变DNA的"可及性"(accessibility),进而影响特定的生理、生化过程。染色质重塑复合体最早在酵母中发现,生化分析表明其至少含有13个亚基。目前植物染色质重塑复合体的组成还未完全解析,但通过对其酵母同源亚基(染色质重塑因子)的研究可从侧面探究植物染色质重塑复合体的功能。同时,还着重讨论了近年来在植物染色质重塑因子研究上取得的结果,以期为植物染色质重塑的作用机制提供启示。     

基于合成致死策略寻找ARID1A突变肝细胞癌的治疗靶点

ARID1A编码的BAF250a蛋白是SWI/SNF(SWItch/Sucrose Non-Fermentable)染色质重组复合物BAF(BRG1-associated factors)的亚基之一,参与改变染色体的结构和可接近性。ARID1A在肝细胞癌(hepatocellular carcinoma,HCC)中的突变率高达13%,但目前尚无有效的治疗药物。本研究旨在利用合成致死策略寻找携带ARID1A突变HCC的治疗新靶标。首先,本研究通过分析ARID1A突变与肿瘤恶性程度的相关性发现ARID1A突变的肿瘤恶性度增加;进而分析Achilles和NCI-60癌症细胞系中ARID1A突变和野生型细胞系的基因表型值(gene phenotype value,GPV)和高表达基因,获得ARID1A突变细胞低GPV和高表达的重叠基因,再扩大样本使用CCLE(Cancer Cell Line Encyclopedia)细胞系的高表达基因进行重叠基因分析;最后并在TCGA(the Cancer Genome Atlas)肝癌数据库中进行筛选,获得116个潜在的ARID1A合成致死基因。本研究运用生物信息学方法计算获得多个ARID1A的潜在合成性致死基因,为ARID1A突变HCC患者提供新的治疗靶点,也为靶向药物研发提供了新靶标和新策略。     

染色质重塑调控生物温度适应性的研究进展

温度是限制物种适应性分布的重要环境因子,对极端环境温度的耐受性决定生物分布和扩散范围,而表观遗传可以提供快速的响应机制,促使生物快速适应极端环境温度。染色质重塑作为表观遗传的重要组成部分之一,其可以通过调控胁迫相关基因的表达从而促进生物适应不良环境条件。本文主要阐述了染色质重塑复合物的分类、组成和染色质重塑的方式,梳理了染色质重塑在生物温度适应性中的研究进展,提出染色质重塑在生物适应不良环境温度过程中发挥重要作用,并对未来染色质重塑与温度适应性研究提出建议。     

肿瘤抑制因子hTid1研究进展

hTid1(human tumorous imaginal disc 1)是果蝇肿瘤抑制因子Tid56的人类同源蛋白。hTid1属于DnaJ蛋白家族成员,主要定位于线粒体基质中,作为Hsp70蛋白的辅助分子伴侣发挥作用。然而,越来越多的文献报道,hTid1可以与线粒体外的许多蛋白相互作用,进而调控细胞内许多的信号通路。该文综述了近年来hTid1蛋白的最新研究进展,并主要从hTid1蛋白的结构和功能、与肿瘤的相关性、与神经系统的联系及在细胞信号通路中的作用等方面进行系统的阐述。     

染色质重塑复合物SAGA及其同源物的功能

基因表达调控是生物体生长发育的一个重要环节.在这一过程中,染色质重塑复合物扮演了非常重要的作用.SAGA是一个至少由20个蛋白组成的不依赖ATP的多功能染色质重塑复合物,它通过对组蛋白H3和H2B氨基末端赖氨酸乙酰化修饰来松动染色质结构,从而促进基因转录的起始.目前,对SAGA及其同源物的研究表明,SAGA及其同源物参与了许多重要的生物学功能,如mRNA输出、DNA损伤修复、胚胎发育、细胞癌变等.     

高等植物中SWI/SNF染色质重塑研究的新进展

染色质重塑是真核生物表观遗传调控的重要方式．通过对染色质物理结构的调节,染色质重塑在高等动植物干细胞的自我更新及分化、器官和个体发育以及肿瘤发生等多种生物学过程中发挥重要作用．近年来,高等动植物染色质重塑方面的研究已经成为表观遗传学研究领域的热点．本综述总结近年来有关高等动植物染色质重塑的重要研究报道,介绍了染色质重塑的结构机制、分析比较了高等动植物染色质重塑复合体的组成及其生物学功能的多样性,并着重综述了高等植物SWI/SNF染色质重塑复合体各组分在调控植物发育与逆境生长等方面的功能,以期为今后植物中染色质重塑的研究提供启示．     

ATP依赖的染色质改构复合物及其作用机制

染色质高度紧密的折叠阻止了转录因子和辅因子与DNA的结合, 因而通过染色质重塑以解除这样的抑制环境, 对于转录活动的正常进行是至关重要的。目前认为, 染色质重塑至少是通过两种机制来完成的, 一种是通过ATP依赖的染色质改构复合物, 另一种是通过对组蛋白尾部进行共价修饰的组蛋白修饰酶复合物。文章结合近年来的研究进展, 对前者进行染色质重塑的机制及两者在基因转录调控过程中如何相互协作等进行了论述。     

TRIM32/USP11 Balances ARID1A Stability and the Oncogenic/Tumor-Suppressive Status of Squamous Cell Carcinoma

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A tumor suppressor DLC1: The functions and signal pathways

Deleted in liver cancer-1 (DLC1), a potential tumor suppressor, acts as a GTPase-activating protein for Rho family members. In many human cancers, the DLC1 expression is frequently downregulated or inactivated, which allows cancer cells to proliferate and disseminate. In this review, we describe the characteristics and other members of the DLC1 family and delineate the signal pathways DLC1 involved in regulating cancer cell growth, colony formation, apoptosis, senescence, autophagy, migration and invasion. In addition, we explore the clinical data of DLC1 and the mechanisms that natural products upregulate the DLC1 expression to inhibit cancer. Despite these insights, many important unanswered questions remain about the exact mechanisms of DLC1-mediated cancer suppression.     

Histone deacetylase HDAC2 silencing prevents endometriosis by activating the HNF4A/ARID1A axis

Endometriosis is the most major cause of chronic pelvic pain in women of reproductive age. Moreover, the involvement of histone deacetylase 2 (HDAC2) has been identified in endometriosis. However, the specific mechanism of HDAC2 remains to be further elusive. Therefore, this study was designed to explore the mechanism of HDAC2 orchestrating hepatocyte nuclear factor 4α/AT-rich interactive domain 1A (HNF4A/ARID1A) axis in endometriosis. Endometriosis cell line hEM15A and clinical endometriosis tissues were obtained, followed by gain- and loss-of-function assays in hEM15A cells. HDAC2, HNF4A and ARID1A expression was detected by immunohistochemistry and Western blot analysis. Cell viability was determined by Cell Counting Kit-8 Assay, invasion by Transwell assay and apoptosis by flow cytometry. HDAC2 enrichment in HNF4A promoter region and HNF4A enrichment in ARID1A promoter region was detected through chromatin immunoprecipitation. Mouse models of endometriosis were established, followed by immunohistochemistry of Ki-67 expression and TUNEL staining of apoptosis in ectopic tissues. HDAC2 was upregulated but HNF4A and ARID1A were downregulated in endometriosis tissues. HDAC2 inhibited HNF4A expression by deacetylation, and HNF4A was enriched in ARID1A promoter region to activate ARID1A. Silencing HDAC2 or overexpressing HNF4A or ARID1A diminished the viability and invasion and augmented the apoptosis of hEM15A cells. HDAC2 silencing reduced the area and weight of endometriosis tissues, suppressed endometriosis cell proliferation and accelerated endometriosis cell apoptosis. The inhibitory action of silencing HDAC2 via HNF4A/ARID1A axis was reproduced in mouse models. Collectively, HDAC2 silencing might upregulate HNF4A via repression of deacetylation to activate ARID1A, thus preventing the occurrence of endometriosis.     

LKB1抑癌机制研究进展

人LKB1(Liver Kinase B1,或Serine-Threonine Kinase 11,STK11)基因的胚系失活突变可导致癌症易感病皮杰氏综合征(Peutz-Jeghers syndrome,PJS),该病患者多发错构瘤息肉且患癌症风险增加。LKB1基因的体细胞突变还广泛地存在于众多类型的恶性肿瘤中,如肺癌、结肠癌和乳腺癌等,因此,LKB1被普遍认为是抑癌基因。LKB1基因的编码产物LKB1是一种丝氨酸/苏氨酸激酶,调节多种细胞生理病理过程。虽然LKB1的抑癌机制尚不完全清楚,但现有的研究表明,对细胞生长增殖、能量代谢和细胞极性等的调控是其抑制肿瘤发生和发展的重要方面。本文就目前已知的LKB1的抑癌机制作一综述。     

Breast cancer suppressor candidate-1 (BCSC-1) is a melanoma tumor suppressor that down regulates MITF

Understanding the molecular aberrations involved in the development and progression of metastatic melanoma (MM) is essential for a better diagnosis and targeted therapy. We identified breast cancer suppressor candidate-1 (BCSC-1) as a novel tumor suppressor in melanoma. BCSC-1 expression is decreased in human MM, and its ectopic expression in MM-derived cell lines blocks tumor formation in vivo and melanoma cell proliferation in vitro while increasing cell migration. We demonstrate that BCSC-1 binds to Sox10, which down regulates MITF, and results in a switch of melanoma cells from a proliferative to a migratory phenotype. In conclusion, we have identified BCSC-1 as a tumor suppressor in melanoma and as a novel regulator of the MITF pathway.