精氨酸甲基转移酶5 在肿瘤发生发展中作用的研究进展

[摘要] 蛋白精氨酸甲基化过程与蛋白的磷酸化、泛素化过程类似,是细胞中常见的翻译后修饰过程。精氨酸甲基转移酶(protein arginine methyltransferase, PRMT)是催化蛋白精氨酸残基氮原子发生甲基化的关键酶。PRMT5 能够催化产生对称性二甲基化精氨酸(symmetrically dimethylated arginine,sDMA),参与调解生命活动。近年来,越来越多的研究表明,PRMT5 与肿瘤的发生发展及肿瘤转移密切相关,并将其作为新靶点进行抗肿瘤药物研究。本文旨在阐述PRMT5 与肿瘤发生发展的相关性和以PRMT5 为靶点的抗肿瘤药物开发及未来的研究发展方向。     

蛋白质精氨酸甲基转移酶在前列腺癌中的研究进展

蛋白质精氨酸甲基转移酶(PRMT)是在真核生物细胞中广泛分布的甲基转移酶,可通过甲基化组蛋白和非组蛋白的精氨酸残基发挥生物学功能。PRMT参与肿瘤的发生、发展,是近年来肿瘤研究领域的新发现,特别是其在前列腺癌中异常表达。PRMT高表达促进前列腺癌细胞的生长和迁移。PRMT能与雄激素受体(AR)相互作用,参与AR信号通路,AR信号通路异常被认为是前列腺癌发生的主要原因之一。此外,PRMT通过甲基化组蛋白激活或抑制基因的表达,通过甲基化非组蛋白参与Wnt信号通路等。     

蛋白精氨酸甲基转移酶5在急性髓系白血病中的研究进展

急性髓系白血病（acute myeloid leukemia,AML）是一种常见的恶性血液肿瘤。表观遗传学修饰可以通过转录后甲基化等方式在AML中发挥关键作用。蛋白精氨酸甲基转移酶5（protein arginine methyltransferase 5，PRMT5）是一种Ⅱ型蛋白精氨酸甲基转移酶，可通过催化作用将S-腺苷甲硫氨酸的甲基转移至精氨酸的胍基氮原子上，形成甲基精氨酸和S-腺苷同型半胱氨酸。近年来研究发现，PRMT5可通过调控肿瘤相关基因转录后甲基化、mRNA剪切等方式促进AML的发生发展。本文主要综述了PRMT5在AML中的研究进展，并总结了多种PRMT5抑制剂对AML的治疗效应。     

CARM1的研究进展及与乳腺癌的关系

组蛋白精氨酸甲基转移酶1（CARM1）,是蛋白质精氨酸甲基转移酶家族（PRMTs）的成员之一,也称为PRMT4。近年有文献报道CARM1是多种肿瘤相关转录因子的共激活因子,在多种肿瘤中表达异常,特别是在乳腺癌中。本文就CARM1在正常组织中的生物学功能、与雌激素依赖型乳腺癌发生发展的关系、在乳腺癌不同分子亚型中的作用及在肿瘤细胞中的功能进行研究和讨论,揭示其在乳腺癌中存在的生物学机制,对乳腺癌的治疗提出了可能性靶点。     

蛋白质精氨酸甲基转移酶5抑制剂的研究进展

DNA甲基化作为一种重要的表观遗传修饰方式,参与调控多种疾病的发生与发展。蛋白精氨酸甲基转移酶5（protein arginine methyltransferases 5,PRMT5）是真核细胞常见的一种催化组蛋白或非组蛋白甲基化修饰的酶,在多种人类恶性肿瘤中均表达上调,研发PRMT5抑制剂可能成为治疗癌症的一个重要途径。本文针对PRMT5的结构特征、肿瘤相关性以及目前报道的抑制剂进行综述,为PRMT5抑制剂的进一步优化奠定基础。     

蛋白质精氨酸甲基转移酶5在肿瘤中的作用及其临床应用

[摘要] 蛋白质精氨酸甲基转移酶5（protein arginine methyltransferase 5,PRMT5）是一种Ⅱ型蛋白质精氨酸甲基转移酶,在胃癌、肝癌、结直肠癌、肺癌和乳腺癌等多种肿瘤中异常表达。异常表达的PRMT5 通过调节细胞周期蛋白、PI3K细胞信号通路等途径影响肿瘤细胞,通过对相关肿瘤抑制基因的调控进而影响肿瘤的发生和发展。本文围绕近年来肿瘤中PRMT5 的最新研究进展,包括对雄激素受体、免疫细胞、E2F-1-Bcl-2 途径、PTEN和P16 等的作用及其机制,并结合目前相关抑制剂的研究,讨论如何在未来临床治疗中靶向PRMT5达到治疗肿瘤的目的。     

PRMT1通过精氨酸甲基化作用修饰剪接因子SF2/ASF

目的:探讨蛋白质精氨酸甲基转移酶1 (protein arginine methyltransferase 1,PRMT1)对剪接因子SF2/ASF (splicing factor 2/alternative splicing factor ) 的甲基化修饰位点。方法：构建SF2/ASF野生型和Arg93/97/109突变体质粒,在体外表达和纯化GST标签的PRMT1、SF2/ASF及其Arg突变体融合蛋白,以甲基化活性实验检测PRMT1对SF2/ASF的甲基化作用及其甲基化修饰位点,以免疫荧光实验观察甲基化修饰对SF2/ASF亚细胞定位的影响。结果：PRMT1对 SF2/ASF有明显的甲基化修饰作用;当Arg93/97/109突变为赖氨酸后,PRMT1对SF2/ASF突变体的甲基化修饰程度明显降低,其中Arg97突变后SF2/ASF甲基化程度减弱最明显。甲基化修饰不影响SF2/ASF的亚细胞定位。结论：发现SF2/ASF是PRMT1新的底物蛋白,Arg93/97/109均为PRMT1的甲基化修饰位点,其中Arg97是主要修饰位点;PRMT1对于SF2/ASF的甲基化修饰并不改变后者细胞内的定位。     

DNA甲基化基因DNMT1的研究进展

DNA甲基转移酶1(DNMT1)是哺乳动物基因组表观遗传修饰中DNA甲基化的关键基因,其编码的蛋白是一种分子量大且功能复杂的酶,具有多种调控功能,参与机体发育过程中干细胞生长、细胞增殖、器官发育、衰老和肿瘤发生等多个生物学过程。本文将对DNMT1基因的结构与分子作用机制进行介绍,并总结其表达调控、生物学功能及其与肿瘤等人类疾病相关的研究进展。     

CARM1在恶性肿瘤中的作用及靶向治疗研究进展

摘 要：辅激活蛋白关联精氨酸甲基转移酶1（coactivator-associated arginine methyltransferase 1,CARM1）是一种Ⅰ型蛋白质精氨酸甲基转移酶,可以催化组蛋白和非组蛋白底物的精氨酸残基不对称二甲基化。越来越多的研究发现CARM1在多种类型的恶性肿瘤中表达水平升高并发挥促癌作用。高表达的CARM1可通过多种机制促进肿瘤的发生及进展,例如影响肿瘤免疫、肿瘤代谢、自噬等。因此,CARM1被认为是一个极具潜力的抗肿瘤靶点,已有研究尝试开发靶向CARM1的小分子抑制剂治疗恶性肿瘤。尽管目前利用CARM1抑制剂治疗恶性肿瘤还处于临床前研究阶段,但在体内外试验中已展现出很好的治疗前景。针对CARM1的靶点干预可能为肿瘤治疗提供新策略。全文主要对CARM1的分子结构、肿瘤生物学功能、分子机制以及CARM1特异性抑制剂进行综述。     

DNA 甲基转移酶在肿瘤发病机制中的研究进展

DNA甲基化是表观遗传学的主要形式,而DNA甲基转移酶（ DNMTs）是DNA甲基化的主要调节酶,DNA甲基转移酶的激活参与了肿瘤的发生和发展过程,同时伴有肿瘤抑制基因的高甲基化沉默和低表达,是病人预后不良的标志;DNA甲基转移酶3b（ DNMT3b）的多态性及吸烟所致的DNMTs表达的改变是肿瘤发生的危险因素,靶向DNMTs治疗由于其细胞毒性小,是当前研究的一个热点。本文就DNA甲基转移酶在肿瘤发病机制中的作用做一综述。     

LKB1 regulates PRMT5 activity in breast cancer

Protein arginine methyltransferase 5 (PRMT5) is the main enzyme responsible for the symmetrical dimethylation of arginine residues on target proteins in both the cytoplasm and the nucleus. Though its activity has been associated with tumor progression in various cancers, the expression pattern of this oncoprotein has been scarcely studied in breast cancer. In the current work, we analyzed its expression in a large cohort of breast cancer patients, revealing higher nuclear PRMT5 levels in ERα-positive tumors and an association with prolonged disease free and overall survival. Interestingly, high PRMT5 nuclear expression was also associated with higher nuclear liver kinase B1 (LKB1), suggesting that a functional relationship may occur. Consistently, several approaches provided evidence that PRMT5 and LKB1 interact directly in the cytoplasm of mammary epithelial cells. Moreover, although PRMT5 is not able to methylate LKB1, we found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1. In addition, modulation of LKB1 expression modified PRMT5 activity, highlighting a new regulatory mechanism that could have clinical implications.     

Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3

Protein arginine methyltransferases (PRMTs) plays critical roles in cancer. PRMT5 has been implicated in several types of tumors. However, the role of PRMT5 in cancer development remains to be fully elucidated. Here, we provide evidence that PRMT5 is overexpressed in colorectal cancer (CRC) cells and patient-derived primary tumors, correlated with increased cell growth and decreased overall patient survival. Arginine methyltransferase inhibitor 1 (AMI-1)strongly inhibited tumor growth, increased the ratio of Bax/Bcl-2, and induced apoptosis in mouse CRC xenograt model. AMI-1 also induced apoptosis and decreased the migratory activity in several CRC cells. In CRC xenografts AMI-1 significantly decreased symmetric dimethylation of histone 4 (H4R3me2s), a histone mark of type II PRMT5, but not the expression of H4R3me2a, a histone mark of type I PRMTs. These results suggest that the inhibition of PRMT5 contributes to the antitumor efficacy of AMI-1. Chromatin immunoprecipitation (ChIP) identified FGFR3 and eIF4E as two key genes regulated by PRMT5. PRMT5 knockdown reduced the levels of H4R3me2s and H3R8me2s methylation on FGFR3 and eIF4E promoters, leading to decreased expressions of FGFR3 and eIF4E. Collectively, our findings provide new evidence that PRMT5 plays an important role in CRC pathogenesis through epigenetically regulating arginine methylation of oncogenes such as eIF4E and FGFR3.     

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.     

SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression

Both lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well-known arginine methyltransferase, was identified as a SMYD4-binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E-cadherin, RBL2, and miR-29b-1-5p. Moreover, miR-29b-1-5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor in vitro and in vivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4-PRMT5 axis as a potential therapeutic target for the treatment of HCC.     

Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4

Programmed cell death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify protein arginine methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that coexpression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy.