更新于：2024-09-19

METTL16

更新于：2024-09-19

基本信息

别名

Methyltransferase 10 domain-containing protein、methyltransferase 16, N6-methyladenosine、Methyltransferase-like protein 16

+ [6]

简介

RNA N6-methyltransferase that methylates adenosine residues at the N(6) position of a subset of RNAs and is involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts (PubMed:28525753, PubMed:30197299, PubMed:30197297, PubMed:33428944, PubMed:33930289). Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs) (PubMed:28525753). In contrast to the METTL3-METTL14 heterodimer, only able to methylate a limited number of RNAs: requires both a 5'UACAGAGAA-3' nonamer sequence and a specific RNA structure (PubMed:28525753, PubMed:30197299, PubMed:30197297). Plays a key role in S-adenosyl-L-methionine homeostasis by mediating N6-methylation of MAT2A mRNAs, altering splicing of MAT2A transcripts: in presence of S-adenosyl-L-methionine, binds the 3'-UTR region of MAT2A mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA, preventing recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production of S-adenosylmethionine synthase (PubMed:28525753, PubMed:33930289). In S-adenosyl-L-methionine-limiting conditions, binds the 3'-UTR region of MAT2A mRNA but stalls due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A (PubMed:28525753). In addition to mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6 snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs (PubMed:28525753, PubMed:29051200, PubMed:32266935). Also able to bind various lncRNAs, such as 7SK snRNA (7SK RNA) or 7SL RNA (PubMed:29051200). Specifically binds the 3'-end of the MALAT1 long non-coding RNA (PubMed:27872311).

关联

100 项与 METTL16 相关的临床结果

登录后查看更多信息

100 项与 METTL16 相关的转化医学

登录后查看更多信息

0 项与 METTL16 相关的专利（医药）

登录后查看更多信息

154

项与 METTL16 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism

Article

作者: Duan, Feifan ; Chen, Shuya ; Zhou, Lei ; Gao, Yu ; Zhang, Yukun ; Wang, Wenjing ; Sheng, Zhiyong ; Wang, Yaju ; Li, Qiang ; Meng, Xiangshu

AbstractPapillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m6A in SCD1 cells, increasing RNA decay via the m6A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC.

2024-08-27·Nucleic Acids Research

U6 snRNA m6A modification is required for accurate and efficient splicing of C. elegans and human pre-mRNAs

Article

作者: Miska, Eric A ; Hencel, Katarzyna ; Simpson, Gordon G ; Scott, Robyn ; Skukan, Roberta ; Metheringham, Carey L ; Akay, Alper ; Haerty, Wilfried ; Shen, Aykut ; Adesina, Aduragbemi S ; Nam, Yunsun ; Parker, Matthew T

Abstractpre-mRNA splicing is a critical feature of eukaryotic gene expression. Both cis- and trans-splicing rely on accurately recognising splice site sequences by spliceosomal U snRNAs and associated proteins. Spliceosomal snRNAs carry multiple RNA modifications with the potential to affect different stages of pre-mRNA splicing. Here, we show that the conserved U6 snRNA m6A methyltransferase METT-10 is required for accurate and efficient cis- and trans-splicing of C. elegans pre-mRNAs. The absence of METT-10 in C. elegans and METTL16 in humans primarily leads to alternative splicing at 5′ splice sites with an adenosine at +4 position. In addition, METT-10 is required for splicing of weak 3′ cis- and trans-splice sites. We identified a significant overlap between METT-10 and the conserved splicing factor SNRNP27K in regulating 5′ splice sites with +4A. Finally, we show that editing endogenous 5′ splice site +4A positions to +4U restores splicing to wild-type positions in a mett-10 mutant background, supporting a direct role for U6 snRNA m6A modification in 5′ splice site recognition. We conclude that the U6 snRNA m6A modification is important for accurate and efficient pre-mRNA splicing.

2024-06-01·Ecotoxicology and Environmental Safety

Effects and mechanisms of N6-methyladenosine RNA methylation in environmental pollutant-induced carcinogenesis

Review

作者: Xu, Zhijie ; Thakur, Abhimanyu ; Liu, Wangrui ; Zhang, Kui ; Li, Tong-Fei ; Yang, Xiaoxin ; Zeng, Shuangshuang ; Yan, Yuanliang ; Gao, Ming

Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m⁶A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m⁶A writers, erasers, and readers, m⁶A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m⁶A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m⁶A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m⁶A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m⁶A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m⁶A modification of AKT1, METTL3-mediated m⁶A-modified oxidative stress, METTL16-mediated m⁶A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m⁶A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.

项与 METTL16 相关的新闻（医药）

2024-06-24

·生物探索

Molecular Cancer | 揭示RNA甲基化如何影响肿瘤免疫：从机制到治疗（综述）

引言 RNA甲基化是一种常见的转录后修饰，在研究领域中引起了广泛关注。它通过调节RNA剪接、翻译、运输和稳定性，对多种生物功能进行调控。值得注意的是，研究表明，RNA甲基化对肿瘤免疫具有显著影响。主要的RNA甲基化类型包括N6-甲基腺嘌呤(m6A)、5-甲基胞嘧啶(m5C)、N1-甲基腺嘌呤(m1A)、N7-甲基鸟嘌呤(m7G)和3-甲基胞嘧啶(m3C)。RNA甲基化参与了肿瘤微环境(TME)的调控。通过影响RNA翻译和稳定性，RNA甲基化通过“写入者”、“擦除者”和“读取者”调节免疫细胞和免疫因子的失调。因此，RNA甲基化在调节肿瘤免疫和介导多种生物行为（包括增殖、侵袭、转移等）中起着关键作用。 6月20日Molecular Cancer发表的综述“The role of RNA methylation in tumor immunity and its potential in immunotherapy”，讨论了几种RNA甲基化的机制和功能，全面概述了它们在肿瘤微环境和免疫细胞中的生物作用和基本机制。通过探讨这些RNA修饰如何介导肿瘤免疫逃逸，还分析了它们在免疫治疗中的潜在应用，为RNA甲基化新靶点的识别和提高癌症免疫治疗效果提供新的见解和策略。 RNA修饰通过对RNA碱基和核糖的化学变化，显著影响基因表达。到目前为止，研究人员已经在各种RNA类别（包括原核生物和真核生物）中鉴定出了超过170种化学修饰。其中，RNA甲基化占所有RNA修饰的60%以上，在转录后基因调控中起着重要作用。主要的RNA甲基化形式包括N1-甲基腺嘌呤(m1A)、N6-甲基腺嘌呤(m6A)、5-甲基胞嘧啶(m5C)、N7-甲基鸟嘌呤(m7G)和3-甲基胞嘧啶(m3C)，这表明它在塑造基因调控的复杂景观中具有广泛存在和重要意义。RNA甲基化由三类蛋白质介导：“写入者”催化甲基基团的添加；“读取者”识别这些修饰；“擦除者”去除这些修饰，每种蛋白质通过独特的机制发挥作用。这些蛋白质调节多种RNA类型和信号通路，包括mRNA、tRNA、长链非编码RNA(lncRNA)、小RNA(sRNA)等。作为一个动态且可逆的过程，RNA甲基化调节着关键的生物过程，如剪接、翻译、运输和RNA稳定性。大量研究表明，RNA甲基化在多种癌症的发生和进展中起着至关重要的作用，包括乳腺癌、肺癌、结直肠癌(CRC)、肝细胞癌(HCC)、胃癌(GC)、食道癌(EC)、前列腺癌(PCa)、膀胱癌、卵巢癌、急性髓性白血病(AML)、胰腺癌等，凸显了它在恶性肿瘤中的关键作用。近年来，许多研究强调了RNA甲基化与各种免疫过程之间的密切关联，特别是在肿瘤免疫背景下。此外，调控蛋白的异常表达与致癌活动和增强的转移特性有关。RNA甲基化还在维持肿瘤微环境(TME)的稳态和代谢重编程中起着关键作用，影响免疫细胞的功能。TME由包括免疫细胞、基质细胞、细胞外基质、血管和其他可溶性因子在内的复杂多细胞基质组成。RNA甲基化通过影响癌基因和转移能力，破坏TME的和谐，损害免疫细胞功能，从而促进肿瘤免疫逃逸。例如，m6A写入者METTL3已知维持高水平的糖酵解，并在HCC中诱导代谢重编程。这种酶还影响巨噬细胞极化、树突状细胞的活化、效应T细胞的分化和增殖以及免疫检查点的表达。这些相互作用展示了RNA甲基化如何将TME和免疫细胞与肿瘤免疫逃逸的机制联系起来。目前，研究人员正在探索可能抑制METTL3和其他RNA甲基化调节因子的潜在抑制剂，希望这些化合物能用于免疫治疗。 RNA甲基化是一种常见的转录后修饰(post-transcriptional modification)，在基因表达调控中扮演着关键角色。近年来，研究人员发现，RNA甲基化不仅在正常生理过程中重要，而且在肿瘤的发生和发展中也起到关键作用。尤其是它在调控肿瘤免疫和免疫逃逸方面的功能，引起了广泛关注。 RNA甲基化的类型与机制目前已知的RNA甲基化类型超过170种，其中最主要的包括N6-甲基腺嘌呤(m6A)、5-甲基胞嘧啶(m5C)、N1-甲基腺嘌呤(m1A)、N7-甲基鸟嘌呤(m7G)和3-甲基胞嘧啶(m3C)。这些修饰通过特定的蛋白质进行调控：写入者(Writers)：如METTL3和METTL14等，催化甲基基团的添加。擦除者(Erasers)：如FTO和ALKBH5等，去除甲基基团。读取者(Readors)：如YTHDF1和IGF2BP1等，识别并结合甲基化修饰，调控RNA的功能。其中，m6A是最常见的RNA甲基化形式，广泛存在于mRNA、rRNA、tRNA、长链非编码RNA(lncRNA)和小RNA(sRNA)中。m6A甲基化调控着RNA的剪接、翻译、稳定性和运输等关键生物过程。 RNA甲基化的机制以及RNA甲基化如何调控RNA的命运和生物功能（Credit: Molecular Cancer） RNA甲基化的写入者(Writers)：m6A：METTL3和METTL14；m5C：NSUN2；m1A： TRMT10A；m7G：METTL1。 RNA甲基化的擦除者(Erasers)：m6A：FTO和ALKBH5。 RNA甲基化的读取者(Readors)：IGF2BP1/2/3、YTHDF1/2/3、YTHDC1/2/3、YBX1、ALYREF、CBC、eIF4E等蛋白质可以识别并结合RNA上的甲基化修饰。 RNA甲基化对RNA命运的调控：RNA甲基化可以调控mRNA的剪接、导出、稳定性、降解和翻译等生物功能。关键蛋白：METTL3 (methyltransferase-like 3)，FTO (obesity-associated protein)，ALKBH5 (AlkB homolog 5)，TET1/2/3 (ten-eleven translocation proteins 1/2/3)，ALKBH1 (α-ketoglutarate-dependent dioxygenase ABH1) RNA甲基化在肿瘤中的作用大量研究表明，RNA甲基化在多种癌症的发生和进展中起着至关重要的作用。例如，m6A写入者METTL3在肝细胞癌(HCC)中维持高水平的糖酵解，并诱导代谢重编程。这种酶还影响巨噬细胞的极化、树突状细胞的活化、效应T细胞的分化和增殖以及免疫检查点的表达。 METTL3在HCC中的作用：研究表明，METTL3通过上调葡萄糖转运蛋白(GLUT1)的表达，促进糖酵解进程，从而为肿瘤细胞的增殖提供必要的能量条件。此外，METTL3还通过调控HIF-1α的表达，促进缺氧条件下肿瘤细胞的存活和增殖。 NSUN2在食道癌中的作用：NSUN2通过稳定GRB2的表达，增强癌细胞的增殖和迁移能力。另有研究表明，NSUN2能够通过调控CDKN1A的表达，抑制脂肪生成，表明NSUN2在肿瘤代谢重编程中也起到重要作用。肿瘤微环境(TME)的组成以及RNA甲基化如何通过缺氧、代谢重编程和酸性环境来促进肿瘤免疫逃逸（Credit: Molecular Cancer）肿瘤微环境的组成：肿瘤微环境包括免疫细胞、基质细胞、细胞外基质、血管和其他可溶性因子。 RNA甲基化在肿瘤免疫逃逸中的作用：缺氧诱导因子(HIF)通过m6A、m5C、m1A和m7G RNA甲基化来调控免疫抑制性TME的形成，并促进肿瘤免疫逃逸。RNA甲基化调控生物代谢，包括葡萄糖代谢、脂质代谢和氨基酸代谢，导致免疫细胞功能障碍和酸性环境的形成，从而促进肿瘤发生、血管生成和肿瘤细胞增殖。这些变化进一步加重组织缺氧，促进肿瘤进展。代谢重编程与肿瘤进展：葡萄糖代谢：通过m6A、m5C、m1A和m7G RNA甲基化调控葡萄糖代谢途径，促进肿瘤细胞的糖酵解；脂质代谢：RNA甲基化调控脂质代谢，影响脂肪酸的合成、降解和储存，促进肿瘤细胞的膜结构和能量生成；氨基酸代谢：RNA甲基化调控非必需氨基酸(NEAAs)和必需氨基酸(EAAs)的代谢，影响肿瘤细胞的生长和免疫逃逸。相互作用与协同作用：缺氧、代谢重编程和酸性环境相互作用，共同促进肿瘤免疫逃逸；缺氧环境激活HIF，进一步调控RNA甲基化，促进肿瘤进展；代谢重编程导致酸性环境的形成，影响免疫细胞功能，加剧肿瘤免疫逃逸。 RNA甲基化与肿瘤免疫 RNA甲基化在肿瘤免疫调控中发挥着重要作用。它通过影响肿瘤微环境(TME)中的免疫细胞和免疫因子的失调，调节肿瘤免疫逃逸机制。主要机制包括：调控免疫细胞功能：RNA甲基化通过调控免疫细胞如巨噬细胞、树突状细胞(DCs)、髓源性抑制细胞(MDSCs)和调节性T细胞(Tregs)的功能，影响肿瘤免疫逃逸。例如，m6A写入者METTL3促进巨噬细胞的M1极化，增强其抗肿瘤能力，而FTO则通过抑制NF-κB信号通路，抑制M1和M2巨噬细胞的极化。调控TME稳态：RNA甲基化通过调控糖酵解、脂肪代谢和氨基酸代谢，影响TME的代谢重编程，进而影响肿瘤免疫。例如，METTL3通过上调GLUT1的表达，促进糖酵解进程，为肿瘤细胞的增殖提供条件。调控免疫检查点：RNA甲基化通过调控免疫检查点如PD-1/PD-L1的表达，影响肿瘤免疫逃逸。研究表明，m6A读取者YTHDF1在DCs中上调MHC-II的表达，增强抗原呈递能力，从而增强免疫反应。 RNA甲基化如何参与肿瘤微环境(TME)的代谢重编程，包括葡萄糖代谢、脂质代谢和氨基酸代谢（Credit: Molecular Cancer） RNA甲基化在代谢重编程中的作用：RNA甲基化调控与糖酵解相关基因（如GLUT1、Gys2、HDGF）和信号通路（如PI3K-AKT、mTORC1、MAPK、Wnt-β catenin、Hedgehog、NF-κB、IL-6/JAK2/STAT3、cGAS/STING）的表达，通过这些调节因子（如METTL1、METTL3、METTL14、NOP2、NSUN2、FTO、ALKBH3、IGF2BP3、YTHDC1）增强Warburg效应。葡萄糖代谢：m6A、m5C和m7G甲基化通过调控糖酵解相关基因和信号通路，促进葡萄糖代谢。例如，METTL3通过上调GLUT1的表达，增强糖酵解进程。脂质代谢：m6A和m5C甲基化加速脂质积累。具体而言，m6A和m5C甲基化调控脂质代谢相关基因（如ACLY和SCD1）的表达，促进脂肪酸的合成和储存。氨基酸代谢：m6A、m5C和m7G甲基化调控谷氨酰胺、精氨酸、蛋氨酸和赖氨酸的代谢。例如，BCAT1（支链氨基酸转氨酶1）在AML中通过重编程BCAA代谢促进癌症发生。代谢重编程的影响：这些甲基化修饰影响肿瘤细胞的免疫原性、增殖、免疫逃逸以及肿瘤进展。例如，m6A读取者IGF2BP3通过稳定PRMT1 mRNA，调控蛋白精氨酸甲基转移酶1（PRMT1）的表达，从而影响肿瘤细胞的功能。 YTHDF1在DCs中的作用：通过敲除YTHDF1基因，研究人员发现DCs中的MHC-II表达显著增加，IL-12的分泌也有所增强，从而提升了适应性免疫反应。 METTL3在MDSCs中的作用：研究发现，敲除METTL3基因能够显著减少MDSCs的积累，从而增强CD8+ T细胞的活化和增殖。 FTO在肿瘤中的作用：FTO抑制剂能够通过抑制肿瘤细胞的糖酵解进程，逆转CD8+ T细胞的活化和效应状态。结合FTO抑制剂和抗PD-L1治疗，有望显著提高抗肿瘤免疫反应。 RNA甲基化如何在肿瘤微环境(TME)中调控免疫细胞的生物功能，包括免疫细胞的分化、发育、浸润、活化、增殖和凋亡（Credit: Molecular Cancer）免疫细胞的分化和发育：RNA甲基化在免疫细胞的分化和发育中起重要作用。例如，m6A和m5C甲基化调控CD8+ T细胞的浸润和活化，并介导其功能障碍。肿瘤相关巨噬细胞(TAMs)的极化：RNA甲基化促进肿瘤相关巨噬细胞(TAMs)向M1型或M2型巨噬细胞的极化；TAMs的M1型巨噬细胞具有抗肿瘤作用，而M2型巨噬细胞则具有促肿瘤作用。树突状细胞(DCs)、髓源性抑制细胞(MDSCs)和调节性T细胞(Tregs)的增殖和浸润：RNA甲基化调控树突状细胞(DCs)、髓源性抑制细胞(MDSCs)和调节性T细胞(Tregs)的增殖和浸润。例如，m6A甲基化通过调控DCs的抗原呈递能力，影响免疫反应。 T细胞的分化和发育：RNA甲基化在T细胞的分化和发育中起重要作用。m1A和m7G甲基化参与CD4+ T细胞和CD8+ T细胞的活化、浸润和增殖，但这些过程中m1A和m7G的具体调控机制尚需进一步研究。 RNA甲基化在肿瘤免疫反应和逃逸中的作用：RNA甲基化通过影响免疫细胞的分化、发育、浸润、活化、增殖和凋亡，调控肿瘤免疫反应和逃逸。例如，m6A和m5C甲基化通过抑制CD8+ T细胞的浸润和活化，介导其功能障碍，从而促进肿瘤免疫逃逸。 RNA甲基化在免疫治疗中的潜力随着对RNA甲基化在肿瘤免疫调控中作用的深入研究，研究人员开始探索其在免疫治疗中的应用潜力。通过靶向RNA甲基化调控蛋白，有望开发出新的免疫治疗策略，提高癌症治疗的效果。靶向METTL3：研究发现，抑制METTL3的表达能够显著减少MDSCs的积累，从而增强CD8+ T细胞的活化和增殖。靶向METTL3的抑制剂有望成为一种新的免疫治疗手段。靶向FTO：FTO作为一种去甲基酶，其抑制剂已被证明能够通过抑制肿瘤细胞的糖酵解进程，逆转CD8+ T细胞的活化和效应状态。结合FTO抑制剂和抗PD-L1治疗，有望显著提高抗肿瘤免疫反应。靶向YTHDF1：抑制YTHDF1的表达能够增强树突状细胞的抗原呈递能力，从而增强免疫反应。研究表明，YTHDF1抑制剂有望提高癌症患者对免疫治疗的响应率。 RNA甲基化如何通过其调控因子调节免疫检查点的表达，并且在急性髓性白血病(AML)中，几种小分子抑制剂联合免疫检查点阻断疗法的应用（Credit: Molecular Cancer）共抑制性受体-配体复合物：包括PD-1/PD-L1、CTLA-4/CD80、VISTA等。这些复合物通过与肿瘤细胞上的相应配体结合，向T细胞传递负性信号，从而抑制T细胞的抗肿瘤反应。共刺激性受体-配体复合物：包括CD40/CD40L、ICOS/ICOSL等。这些复合物通过与肿瘤细胞上的相应配体结合，向T细胞传递正性信号，从而增强T细胞的抗肿瘤反应。 RNA甲基化调控免疫检查点的机制：m6A和m5C甲基化通过调控免疫检查点的表达、翻译和稳定性，影响其对免疫治疗的敏感性。例如，免疫检查点PD-1、CTLA-4、ICOS、VISTA和CD40L通过与肿瘤细胞上的相应配体结合，触发T细胞反应的负性或正性信号。 RNA甲基化的调控因子：参与调控免疫检查点的RNA甲基化调控因子包括METTL3、ALKBH5、FTO和METTL16等。这些调控因子通过调节m6A和m5C甲基化，影响免疫检查点的功能。小分子抑制剂的应用：针对METTL3和FTO的几种小分子抑制剂，包括STM2457、Alk-04、FB23-2和Dac51等，可以抑制m6A甲基化过程，并应用于AML的治疗。这些小分子抑制剂联合免疫检查点阻断疗法，有望提高AML患者的治疗效果。 RNA甲基化在肿瘤免疫中的作用及其在免疫治疗中的潜力正逐渐被揭示。通过靶向RNA甲基化调控蛋白，有望开发出新的免疫治疗策略，提高癌症治疗的效果。未来的研究需要进一步探索RNA甲基化在肿瘤免疫中的具体机制，并开发更多的RNA甲基化调控剂，以期在临床上取得突破。参考文献 Li Y, Jin H, Li Q, Shi L, Mao Y, Zhao L. The role of RNA methylation in tumor immunity and its potential in immunotherapy. Mol Cancer. 2024 Jun 20;23(1):130. doi: 10.1186/s12943-024-02041-8. PMID: 38902779; PMCID: PMC11188252. https://molecular-cancer-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s12943-024-02041-8 责编|探索君排版|探索君转载请注明来源于【生物探索】 End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell 综述

免疫疗法信使RNA

2024-04-10

·Science Daily

A promising target for new RNA therapeutics now accessible

Only recently, a new era in medicine began with the first RNA vaccines. These active substances are modified RNAs that trigger immune responses of the human immune system. Another approach in RNA medicine targets the body's own RNA and its protein modulators by specifically tailored active substances. Only recently, a new era in medicine began with the first RNA vaccines. These active substances are modified RNAs that trigger immune responses of the human immune system. Another approach in RNA medicine targets the body's own RNA and its protein modulators by specifically tailored active substances. Peng Wu, research group leader at the Chemical Genomics Centre at the Max Planck Institute of Molecular Physiology in Dortmund, and colleagues, have now developed the first small-molecule inhibitors against the RNA-modifying enzyme METTL16. The methyltransferase is responsible for the regulation of different RNAs and is a promising anti-cancer target. The new findings lay the foundation for a comprehensive investigation of the role of METTL16 in health and disease and are a step closer towards the development of therapeutic agents targeting such RNA modifiers. RNA has long been considered only as a passive messenger in the cell, produced by DNA transcription to transfer genetic information to the protein factories, the ribosomes. However, it has turned out, that RNA does much more than that. In addition to the coding DNA just described, there is also non-coding DNA controlling many cellular processes by regulating the activity of genes at many levels. No less than a dozen RNA classes have been identified nowadays. RNAi for example, is used by the cell to degrade particular RNA targets to silence genes, when it comes to fighting foreign viral DNA. Readers, writers, and erasers RNA interacts with a plethora of biomolecules, not only other RNAs or DNA but also proteins and metabolites. The resulting regulatory complexes control diverse vital cellular processes and errors can cause diseases. RNA's fate is determined by chemical modifications that affect its stability, structure and interactions and thereby its fate. More than 170 distinct RNA modifications have been described so far. The most abundant is the methylation on the N6-position of the RNA-nucleotide adenosine (m6A). It allows the cell to quickly respond to environmental changes by initiating appropriate cellular responses, such as division, differentiation or migration. This is why RNA-methylation needs to be tightly controlled, taken care of by a set of proteins: "writers" deposit, "readers" recognize and "erasers" remove the methyl group. New substance prevents writing to RNA Aberrant RNA methylation has been associated with cancers and other human diseases, making "writers" an attractive therapeutic target. Only a handful of RNA m6A writers have been identified so far. And only for one of them, METTL3, potent inhibitors have been reported. These molecules prevent the writer from absorbing the ink, the biomolecule S-adenosyl methionine (SAM). The group of Peng Wu has now identified the first inhibitor of the writer METTL16. However, in contrast to the before-mentioned inhibitors, it showed a different mode of action: it prevents the interaction of METTL16 with RNA. The scientists were able to identify this new type of inhibitor by developing an assay evaluating the disruption between METTL16 and a fluorophore-labeled mRNA substrate. "Certain cancer cells have elevated writer levels and are also more vulnerable to reduction of SAM levels, which makes them promising anticancer targets. However, the exact biological consequences of METTL16's binding to RNA substrates are not yet clearly determined. With our work, we lay the foundation for a better investigation of the role of METTL16 in disease and health, but also for the development of novel RNA-targeting therapeutics," says Peng Wu.

疫苗siRNA信使RNA

2023-07-17

·生物谷

中国科技大学研究者们揭示了METTL16促进糖酵解代谢重编程与结直肠癌进展

结直肠癌(CRC)是人类第四大常见恶性肿瘤，也是全球第三大癌症相关死亡原因。结直肠癌是一种多因素疾病，涉及遗传、遗传、环境和生活方式等危险因素。结直肠癌(CRC)是人类第四大常见恶性肿瘤，也是全球第三大癌症相关死亡原因。结直肠癌是一种多因素疾病，涉及遗传、遗传、环境和生活方式等危险因素。大多数结直肠癌是散发性的，WNT、EGFR、P53、转化生长因子-β信号通路的突变顺序累积，APC、KRAS、BRAF和DNA错配修复基因被发现导致结直肠癌的发生和发展。除了这些遗传事件，详尽的转录分析显示，根据独特的克隆性、间质和免疫依赖性，结直肠癌的分子分类具有共识，有四种共识的分子亚型。这些共有的分子亚型概括了在结直肠癌中观察到的异质性，并预测了靶向治疗的反应。所有这些都极大地促进了对结直肠癌的诊断和治疗。然而，尤其是在晚期，由于缺乏早期诊断和有效的干预措施，结直肠癌变得难以治疗，导致转移，预后较差。这些糟糕的治疗结果突出表明，需要更好地了解导致结直肠癌启动、进展和扩散的机制。图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1186/s13046-023-02732-y 近日，来自中国科学技术大学的研究者们在J Exp Clin Cancer Res杂志上发表了题为“METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression”的文章，该研究结果表明，METTL16/SOGA1/PDK4轴可能是治疗结直肠癌的有效靶点。糖酵解是癌症的关键标志，并维持恶性肿瘤的发生和发展。N6-甲基腺苷(M6A)修饰在糖酵解中的作用在很大程度上是未知的。本研究探讨了M6A甲基转移酶METTL16在糖酵解代谢中的生物学作用，揭示了结直肠癌发生发展的新机制。研究者们用生物信息学和免疫组织化学(IHC)方法评价METTL16的表达和预后价值。分析METTL16在体内和体外对结直肠癌进展的生物学作用。糖酵解代谢实验验证METTL16和自噬葡萄糖抑制因子(SOGA1)的生物学功能。通过蛋白质/RNA稳定性、RNA免疫沉淀(RIP)、共免疫沉淀(Co-IP)和RNA下拉实验，探讨了其可能的分子机制。 SOGA1是METTL16的直接下游靶点，参与METTL16介导的糖酵解和结直肠癌进展。METTL16通过结合“阅读器”蛋白胰岛素样生长因子2mRNA结合蛋白1(IGF2BP1)显著增强SOGA1的表达和mRNA的稳定性。随后，SOGA1促进AMPK复合体的泛素化，抑制AMPK的表达和磷酸化，从而上调控制糖代谢的关键蛋白丙酮酸脱氢酶激酶4(PDK4)。此外， YY1可通过直接与其启动子结合而转录抑制结直肠癌细胞中METTL16的表达。临床资料表明，METTL16的表达与SOGA1、PDK4呈正相关，与结直肠癌患者的预后不良有关。 METTL16促进的SOGA1 M6A修饰在CRC进展中的机制总结图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1186/s13046-023-02732-y 本研究结果表明，METTL16在结直肠癌进展中具有促进肿瘤的作用。METTL16在结直肠癌组织中表达上调，与结直肠癌患者的预后不良有关。从机制上讲，METTL16/SOGA1/PDK4信号轴通过诱导糖酵解促进结直肠癌进展。这一发现为探索新的结直肠癌诊断生物标记物和治疗靶点提供了新的见解。（生物谷 Bioon.com）参考文献 Wei Wei et al. METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression. J Exp Clin Cancer Res. 2023 Jun 20;42(1):151. doi: 10.1186/s13046-023-02732-y.