组蛋白赖氨酸甲基转移酶NSD3在肿瘤发生中的作用

NSD3是具有致癌作用的组蛋白赖氨酸甲基转移酶（HKMTases）NSD（核受体结合SET结构域蛋白）家族的一员。近期许多研究表明NSD3在乳腺癌、急性髓性白血病、坚果中线癌、肺癌等多种恶性肿瘤中有促进肿瘤发生的作用,可与NUP98、NUT融合或与BRD4、CHD8、MYC等相互作用,形成致癌复合物;也可以通过调控H3K36me2水平或EGFR（K721）甲基化,加速细胞周期进程,促进肿瘤发生。NSD3不仅参与肿瘤的发生,还与肿瘤的不良预后及侵袭能力有关。本文对NSD3最新的研究进展进行归纳总结,探讨NSD3在肿瘤发生中的作用及潜在的应用前景。      

组蛋白赖氨酸甲基转移酶SET8 对蛋白的甲基化修饰及与肿瘤相关性的研究进展*

组蛋白赖氨酸甲基转移酶SET 8 属于SET 基因家族成员,是目前发现的唯一可以特异性催化H 4 赖氨酸20单甲基化（H 4K 20me1）的赖氨酸甲基转移酶（KMTs）;此外,SET 8 还可甲基化p53、TWIST 、Wnt及ERα 等非组蛋白,并通过调节转录过程影响相应基因的表达,进而参与调控细胞周期、染色质固缩和DNA 的复制。有研究提示,SET 8 的单核苷酸多态性与多种肿瘤的发生发展有潜在的相关性。本文就SET 8 对组蛋白和非组蛋白的修饰、microRNA对SET 8 的调节及SET 8 与肿瘤相关性的研究进展进行了综述,旨在为揭示肿瘤的发病机制和筛选治疗靶点提供帮助。      

转移相关基因-2调控肿瘤侵袭转移的研究

转移相关基因-2（MTA2）是转移相关基因家族成员之一,其蛋白质序列及功能结构域编码序列与MTA1具有高度同源性。MTA2参与构成核小体重构及组蛋白去乙酰化酶（NuRD）复合物,并可与多种转录因子相互作用,参与基因转录调控。MTA2在多种恶性肿瘤中异常表达,并与肿瘤恶性生物学行为密切相关,提示MTA2在肿瘤发生、发展过程中发挥重要作用。本文将对MTA2在肿瘤中的表达情况、生物学功能以及在肿瘤侵袭、转移中的相关分子机制等进行综述。     

EZH2与肿瘤的关系

果蝇zeste基因增强子同源物2（EZH2）通过催化组蛋白H3第27位赖氨酸三甲基化抑制基因表达。在前列腺癌、乳腺癌、膀胱癌及胃癌等多种肿瘤中都有高表达,与肿瘤的恶性进程、侵袭性、转移能力关系密切。随着对其在肿瘤中分子功能、上下游调控机制和临床病理特点的深入了解,EZH2有望做为靶点,为肿瘤治疗提供新的途径。     

组蛋白三甲基转移酶SETD2与肿瘤发生发展的关系

SETD2是哺乳动物中唯一的组蛋白H3K36的特异性三甲基转移酶,它的编码基因位于第三号染色体的3p21.31区域.SETD2蛋白是一个230 kD、含有SET结构域的蛋白,最早是由人造血干细胞分离的,也被认为是与亨廷顿病的发病机制相关.它是生物转录延伸过程中的重要组成部分,能够与RNA聚合酶Ⅱ的最大亚基Rbp1结合,参与基因的转录延伸.SETD2还能通过编码区的去乙酰化抑制转录起始的频率以保证基因转录的高保真度,从而预防肿瘤的发生;同时SETD2也能激活转录因子53及下游凋亡靶基因发挥抑癌作用.SETD2在DNA修复方面也具有重要作用,它是人错配基因修复和人同源基因修复过程中不可缺少的重要部分.已经有研究表明在多种肿瘤中SETD2均发生了突变,包括肾透明细胞癌、小儿晚期神经胶质瘤、急性T淋巴细胞白血病等,对某些特定肿瘤的分期和预后也有显著影响.本文将介绍SETD2在人体内的多种功能,并对其在肿瘤发生发展中的作用机制进行综述.     

MMSET在多发性骨髓瘤中的研究进展

多发性骨髓瘤(MM)是一种来源于终末分化的B淋巴细胞恶性肿瘤,以大量浆细胞的克隆性增生为显著特点.组蛋白甲基化是由组蛋白甲基转移酶催化的一种重要的表观遗传学调控方式,影响基因表达和细胞功能.MM中存在细胞遗传学和表观遗传学调节异常,其发生与染色体频繁易位有关,其中t(4;14)(p16;q32)易位导致组蛋白甲基转移酶MMSET (multiple myeloma SET domain)过表达,并且伴随较差的预后.MMSET可催化组蛋白H3、H4的赖氨酸位点发生甲基化,并通过与多种蛋白的相互作用或对靶基因的调控而发挥致癌作用.MMSET及其相关信号分子有望成为潜在的治疗靶点,对MM中MMSET作用和调控机制的研究和探索,将推动靶向治疗药物的发展,为MM的治疗提供新策略.     

组蛋白单甲基转移酶SET8在肿瘤中的调节作用

SET8（PR-set7、SETD8或KMT5A）是目前发现的唯一的组蛋白H4赖氨酸20单甲基转移酶，调节细胞周期的正常运转。SET8的异常表达能够促进肿瘤的增殖、侵袭和转移，可预测肿瘤的不良预后。同时，SET8还能影响肿瘤的能量代谢，促进肿瘤的发生、发展。现就SET8在肿瘤中的作用予以综述，探讨其调控机制及靶向治疗的前景。     

EZH2与肿瘤的关系

 EZH2是PRC2的一个亚基,通过催化组蛋白H3第27位赖氨酸三甲基化抑制基因表达。在前列腺癌、乳腺癌、膀胱癌及胃癌等多种肿瘤中都有高表达,与肿瘤的恶性进程、侵袭性、转移能力关系密切。随着对其在肿瘤中分子功能、上下游调控机制、临床病理特点的深入了解,EZH2有望做为靶点,为肿瘤治疗提供新的途径。     

LSD1在肿瘤中的研究进展及其抑制剂的开发现状

在肿瘤的发生、发展过程中,遗传物质的异常改变发挥了重要作用,但随着表观遗传学的出现,改变了人类对遗传信息的认知,表观遗传学逐渐成为肿瘤研究领域中的热点。组蛋白去甲基化酶1(LSD1)是第1个被发现的组蛋白去甲基化酶,依赖于FAD的单胺氧化酶,可以催化组蛋白赖氨酸H3K4和H3K9去甲基化,启动或抑制基因的转录。目前研究证实,LSD1在多种肿瘤中高表达并与肿瘤的发生及预后密切相关。LSD1对肿瘤的增殖、侵袭和转移起重要的调控作用,因此逐渐成为潜在的抗肿瘤靶点。本文将对LSD1在肿瘤领域的研究进展及其抑制剂在肿瘤中的应用作一综述。     

SETD8在肿瘤发生发展和免疫调节中作用及机制的研究进展

SETD8/SET8/Pr-SET7/KMT5A是唯一已知的催化组蛋白H4K20甲基化的赖氨酸单甲基转移酶（H4K20me1），参与组蛋白翻译后修饰，染色质和细胞核功能的调节，对多种细胞生命活动产生了重要影响。临床上越来越多的证据表明，SETD8与癌症分期和不良预后密切相关，并参与免疫调节。因此，明确SETD8在肿瘤与免疫调节中的作用，将为肿瘤治疗提供更多理论依据。现对SETD8在肿瘤发生发展和免疫调节中的作用机制予以综述。     

Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

The histone demethylase lysine‐specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48‐linked deubiquitin and stability. Interestingly, we found c‐Myc was a key downstream effector of the USP1‐KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.     

Enhancer of zeste homologue 2 plays an important role in neuroblastoma cell survival independent of its histone methyltransferase activity

Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed. We identified a neuroblastoma patient with a regional 7q36 gain, encompassing the enhancer of zeste homologue 2 (EZH2) gene. EZH2 is the histone methyltransferase of lysine 27 of histone H3 (H3K27me3) that forms the catalytic subunit of the polycomb repressive complex 2. H3K27me3 is commonly associated with the silencing of genes involved in cellular processes such as cell cycle regulation, cellular differentiation and cancer. High EZH2 expression correlated with poor prognosis and overall survival independent of MYCN amplification status. Unexpectedly, treatment of 3 EZH2-high expressing neuroblastoma cell lines (IMR32, CHP134 and NMB), with EZH2-specific inhibitors (GSK126 and EPZ6438) resulted in only a slight G1 arrest, despite maximum histone methyltransferase activity inhibition. Furthermore, colony formation in cell lines treated with the inhibitors was reduced only at concentrations much higher than necessary for complete inhibition of EZH2 histone methyltransferase activity. Knockdown of the complete protein with three independent shRNAs resulted in a strong apoptotic response and decreased cyclin D1 levels. This apoptotic response could be rescued by overexpressing EZH2ΔSET, a truncated form of wild-type EZH2 lacking the SET transactivation domain necessary for histone methyltransferase activity. Our findings suggest that high EZH2 expression, at least in neuroblastoma, has a survival function independent of its methyltransferase activity. This important finding highlights the need for studies on EZH2 beyond its methyltransferase function and the requirement for compounds that will target EZH2 as a complete protein.     

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem- and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients’ tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.     

Concepts of epigenetics in prostate cancer development

Substantial evidence now supports the view that epigenetic changes have a role in the development of human prostate cancer. Analyses of the patterns of epigenetic alteration are providing important insights into the origin of this disease and have identified specific alterations that may serve as useful diagnostic and prognostic biomarkers. Examination of cancer methylation patterns supports a stem cell origin of prostate cancer. It is well established that methylation of GSTpi is a marker of prostate cancer, and global patterns of histone marking appear to be linked to cancer prognosis with levels of acetylated histones H3K9, H3K18, and H4K12, and of dimethylated H4R3 and H3K4, dividing low-grade prostate cancer (Gleason 6 or less) into two prognostically separate groups. Elevated levels of several components of the polycomb group protein complex, EZH2, BMI1, and RING1, can also act as biomarkers of poor clinical outcome. Many components of the epigenetic machinery, including histone deacetylase (whose expression level is linked to the TMPRSS2:ERG translocation) and the histone methylase EZH2, are potential therapeutic targets. The recent discovery of the role of small RNAs in governing the epigenetic status of individual genes offers exciting new possibilities in therapeutics and chemoprevention.