肿瘤细胞中染色质修饰与代谢的相互调控

肿瘤细胞中表观遗传的改变可影响癌基因和抑癌基因的表达水平;此外,肿瘤细胞中伴有的葡萄糖消耗增加、氧化磷酸化减少以及大量乳酸生成等代谢重编程现象,为生物合成提供了更多的中间代谢产物,并重新平衡了肿瘤细胞的氧化还原状态。而表观遗传的改变和代谢重编程均是肿瘤细胞的重要标志。随着研究的不断深入,发现肿瘤细胞代谢和表观遗传（主要是染色质修饰）之间存在着重要的双向调节机制。代谢重编程可影响染色质修饰酶所需的辅助因子,产生的肿瘤代谢产物作为染色质修饰酶的激动剂或拮抗剂,影响染色质修饰;反之,染色质修饰可以直接调控代谢酶的表达,或者改变参与细胞代谢控制的级联信号转导来调节细胞代谢。因此,代谢与表观遗传通过相互调控影响着细胞增殖、转移和多能性,并在肿瘤发生、发展中发挥关键作用。在这篇综述中,我们总结了肿瘤细胞中染色质修饰和代谢相关的最新发现及相互调控机制,以期揭示其在肿瘤发生、发展中的潜在作用,为发展基于肿瘤表观遗传修饰和代谢的靶向治疗方案提供新策略。     

组蛋白去乙酰化酶抑制剂在卵巢癌中的研究进展

摘 要：研究发现在基因的核苷酸序列不发生改变的情况下,基因表达发生的可遗传变化即表观遗传改变与卵巢癌的发生,发展密切相关。近年来,组蛋白去乙酰化酶抑制剂因主要抑制组蛋白去乙酰化酶功能,影响表观遗传改变,在卵巢癌细胞中具有抑制肿瘤生长、分化、促进癌细胞凋亡等作用备受关注。全文就组蛋白去乙酰化酶抑制剂在卵巢癌中的研究进展作一综述。     

肿瘤代谢研究新进展

与正常细胞相比，肿瘤细胞因其基因或者表观遗传的改变，导致许多代谢通路发生紊乱。正常细胞发生恶化过程中，不仅糖代谢通路发生异常，线粒体生物合成、氨基酸代谢、脂代谢等其他代谢通路也会发生变化。这些代谢变化对肿瘤的发生发展以及临床靶向治疗具有重要的意义。     

异柠檬酸脱氢酶基因突变在脑胶质瘤中的研究进展

异柠檬酸脱氢酶1（IDH1）基因突变在神经胶质瘤中的研究备受关注。IDH1突变导致酶原有活性下降,同时获得将α-酮戊二酸转化为2-羟戊二酸的新功能,并改变了胶质瘤的表观遗传学特征,使胶质瘤代谢重编程,破坏胶质瘤氧化还原稳态。本文简述了IDH1突变在胶质瘤中的机制、诊断价值、预后判断和靶向治疗的国内外研究进展,为IDH1突变深入研究、进一步了解胶质瘤病因及干预措施打下基础,亦为胶质瘤分子水平分类和治疗提供新思路。     

骨肉瘤表观遗传研究进展

表观遗传改变不同于基因突变引起DNA序列的永久改变,它不改变基因编码序列。表观遗传调节诱导DNA双螺旋结构的改变和调节基因编码序列上游启动子区域转录因子的进入。表观遗传调节形式包括组织特异的DNA甲基化,组蛋白修饰,microRNA的调节。肿瘤是由遗传和表观遗传渐进性异常所致的一种疾病,该模式可被影响到基因转录的特定启动子状态改变和染色体结构整体改变所映证。表观遗传学在骨肉瘤发生发展过程中作用增加了对这一疾病病理机制的理解,然而,骨肉瘤的发生机制非常复杂且目前尚不完全清楚。因此,需要不断加深对骨肉瘤发生发展和转移机制的研究,以获得新的治疗方法。在骨肉瘤细胞中,现已发现表     

m6A修饰在神经胶质瘤中的研究进展

N6-甲基腺苷(N6-methyladenosine, m6A)是真核细胞中发现的分布最广、含量最丰富的mRNA修饰方式之一。m6A甲基转移酶和去甲基化酶共同调控此过程,在表观遗传修饰水平调控原癌基因、抑癌基因等的表达来影响肿瘤的发生发展。本文综述了m6A调节酶的动态特性,如甲基转移酶、去甲基化酶和m6A结合蛋白,并指出这些蛋白在调节神经胶质瘤基因表达、细胞代谢和癌症发展中的作用。为神经胶质瘤的诊断和靶向治疗提供新的见解。     

脑胶质瘤与铁死亡研究进展

摘 要：基于脑胶质瘤发病过程中的信号通路寻找治疗靶点成为探索脑胶质瘤新型治疗方式的重点领域。铁死亡是一种由脂质过氧化驱动的铁依赖性的细胞死亡方式,已被证实其参与多种肿瘤（包括脑胶质瘤）的发生及进展进程。全文回顾铁死亡的经典代谢途径,总结已有研究中常用的铁死亡诱导剂、抑制剂以及脂质过氧化的评估方法,梳理铁死亡与脑胶质瘤相关研究中的最新发现,包括铁死亡关键调节因子在脑胶质瘤中的表达情况、脑胶质瘤生理环境对铁死亡的影响及脑胶质瘤治疗药物与铁死亡的关系等,为脑胶质瘤的靶向治疗药物研发提供参考。     

乙酰辅酶A代谢在肿瘤表观遗传调控中的研究进展

肿瘤发生发展过程中乙酰辅酶A代谢发生了重编程,为肿瘤的快速生长提供了合成代谢原料。近期多项研究成果证实了肿瘤细胞内乙酰辅酶A还可以通过介导组蛋白乙酰化修饰而行使信号转导功能。在此基础上,本文将从以下三方面对乙酰辅酶A代谢功能及其在肿瘤表观遗传调控及机制方面进行综述:概述乙酰辅酶A的来源及功能;简述肿瘤中乙酰辅酶A与乙酸盐代谢的关系;简述肿瘤细胞乙酰辅酶A代谢酶调控组蛋白乙酰化,影响肿瘤表观遗传改变的最新研究进展,并阐明癌症中靶向乙酰辅酶A关键酶的抑制剂的开发情况。     

脑胶质瘤免疫微环境的研究进展

脑胶质瘤是最常见的中枢神经系统原发性肿瘤,由于存在血脑屏障及其独特的组织器官区域免疫特性,对脑组织免疫微环境与疾病发生发展的相关性研究显得尤为重要。本文将聚焦于生理与病理状态下脑局部免疫微环境的改变,通过对脑胶质瘤局部的各类免疫细胞、免疫分子的作用及机制的介绍,阐明脑胶质瘤局部免疫微环境的抑制效应促进了肿瘤的生长;通过对脑胶质瘤局部免疫微环境的调控和干预,期望改善或逆转上述负性作用,为脑胶质瘤的免疫及综合治疗提供依据。     

组蛋白去乙酰化酶抑制剂对神经胶质瘤的作用研究

正常细胞的分化以及代谢行为的调节依赖组蛋白乙酰基转移酶和组蛋白去乙酰化酶之间的平衡。一旦这种平衡关系被打破,细胞或组织就容易发生癌变,神经胶质瘤也不例外。神经胶质瘤是一种恶性度高且预后极差的颅内肿瘤,其作用机制尚不明确且呈浸润性生长。因此在治疗手段方面尚无行之有效的方法。组蛋白去乙酰化酶抑制剂作为一种新型的化疗药物为胶质瘤的治疗提供了新的方向。它通过阻碍细胞周期、诱导细胞分化和凋亡以及抑制肿瘤血管生成来抑制神经胶质瘤的生长和增殖。本文旨在从化学结构特点和对神经胶质瘤作用机制两方面阐述组蛋白去乙酰化酶抑制剂．并对新的一类组蛋白去乙酰化酶抑制剂丙戊酸及其衍生物的研究作一综述．     

Advances in genetic and epigenetic analyses of gliomas: a neuropathological perspective

Gliomas, the most common malignant primary brain tumors, are universally fatal once they progress from low-grade into high-grade neoplasms. In recent years, we have accumulated unprecedented data about the genetic and epigenetic abnormalities in gliomas; yet, our appreciation of how these deadly tumors arise is still rudimentary. One of the major deterrents in understanding gliomagenesis is the remarkably complex and heterogeneous molecular composition of gliomas, as well as their ability to change phenotypically as they progress and recur. In the past decade, several monumental studies have begun to define better glioma heterogeneity. Four distinct molecular subgroups have emerged: proneural, classical, mesenchymal, and neural; which have unique gene expression signatures and prognostic significance. Of these, gliomas of the proneural subtype, which encompass most grade II/III diffuse gliomas and secondary glioblastomas and often carry isocitrate dehydrogenase (IDH) mutations, have emerged as a distinct tumor subclass with a notably superior prognosis. Important molecular markers with prognostic relevance, such as mutant IDH1/2, have already been incorporated into clinical neuropathological practice. The recent molecular discoveries in gliomas have also emphasized the intimate link between epigenetics and genetics in gliomagenesis. Several of the novel genetic mutations described are responsible for distinct epigenetic remodeling in gliomas, the mechanisms of which are currently being elucidated. Importantly, these epigenetic and genomic alterations represent new and exciting drug targets for future therapeutic interventions in our continuous fight with this fatal malignancy.     

Epigenetic dysregulation in glioma

Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome‐wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.     

Nucleotide-metabolism and chromosome alterations in human-malignant melanoma xenografts

The karyotypes of human melanomas exhibit multiple chromosome alterations. Recurrent deletions of 9p, 10q and 14q arms, which carry genes encoding for enzymes of purine metabolism, were also found in human gliomas, another neuroectodermal tumor previously studied for both cytogenetics and nucleotides metabolism. Postulating that this metabolism might also be modified in melanomas, the activities of eleven enzymes involved in catabolic and synthetic pathways of purine metabolism were measured, in addition to two enzymes of the pyrimidine synthesis. Assays were performed on six melanoma mestastases, five nodal and one cutaneous, after transplantation into nude mice. The purine metabolism was characterized by a more active catabolic than synthetic pathway, a possible imbalance between de novo and salvage pathways for adenylates synthesis, rather in favor of the de novo pathway, and a more active adenylate than guanylate synthesis. The skin metastasis exhibited quite different cytogenetic and metabolic patterns, when compared to the nodal metastases. Considering the relationships between cytogenetic and metabolic data, low activities of methylthioadenosine phosphorylase, adenosine kinase, adenosine monophosphate deaminase, nucleoside phosphorylase and 5'-nucleotidase were observed in melanomas, as well as frequent losses of 9p, 10q, Ip, 14q and 6q arms respectively carrying genes encoding for these enzymes, most of these rearrangements were confirmed by chromosome painting. The two enzymes exhibiting the highest activities were adenosine deaminase and adenylosuccinate lyase, encoded by genes mapped on chromosomes 20 and 22 respectively, frequently in excess in melanomas. Thus, for these tumors, the metabolic pattern roughly parallels the cytogenetic profile, even if the absence of case to case correlation suggests that gene dosage effect, if it occurs, is not the only parameter involved. The main enzymatic and cytogenetic difference between melanomas and gliomas, concerns both adenylosuccinate lyase activity and the balance of chromosome 22, high in melanomas and low in gliomas.     

Precision medicine driven by cancer systems biology

Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance.     

Targeting the epigenome for treatment of cancer

Cancer genome analyses have revealed that the enzymes involved in epigenetic gene regulation are frequently deregulated in cancer. Here we describe the enzymes that control the epigenetic state of the cell, how they are affected in cancer and how this knowledge can be exploited to treat cancer with a new arsenal of selective therapies.