更新于：2024-05-01

YTHDF2

YTH N6-methyladenosine RNA binding protein 2

更新于：2024-05-01

基本信息

别名

CAHL、CLL-associated antigen KW-14、DF2

+ [7]

简介

Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:24284625, PubMed:26046440, PubMed:26318451, PubMed:32492408). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:22575960, PubMed:24284625, PubMed:32492408, PubMed:25412658, PubMed:25412661). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the context (PubMed:24284625, PubMed:26046440, PubMed:27558897, PubMed:30930054, PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). M6A-containing mRNAs containing a binding site for RIDA/HRSP12 (5'-GGUUC-3') are preferentially degraded by endoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRP complex (PubMed:30930054). Other m6A-containing mRNAs undergo deadenylation via direct interaction between YTHDF2 and CNOT1, leading to recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs (PubMed:27558897). Required maternally to regulate oocyte maturation: probably acts by binding to m6A-containing mRNAs, thereby regulating maternal transcript dosage during oocyte maturation, which is essential for the competence of oocytes to sustain early zygotic development (By similarity). Also required during spermatogenesis: regulates spermagonial adhesion by promoting degradation of m6A-containing transcripts coding for matrix metallopeptidases (By similarity). Also involved in hematopoietic stem cells specification by binding to m6A-containing mRNAs, leading to promote their degradation (PubMed:30065315). Also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets (By similarity). Inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thereby restraining neural differentiation (PubMed:32169943). Regulates circadian regulation of hepatic lipid metabolism: acts by promoting m6A-dependent degradation of PPARA transcripts (PubMed:30428350). Regulates the innate immune response to infection by inhibiting the type I interferon response: acts by binding to m6A-containing IFNB transcripts and promoting their degradation (PubMed:30559377). May also act as a promoter of cap-independent mRNA translation following heat shock stress: upon stress, relocalizes to the nucleus and specifically binds mRNAs with some m6A methylation mark at their 5'-UTR, protecting demethylation of mRNAs by FTO, thereby promoting cap-independent mRNA translation (PubMed:26458103). Regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts (PubMed:32267835). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31388144, PubMed:31292544, PubMed:32451507, PubMed:31642031). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544). May also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing (PubMed:31815440). (Microbial infection) Promotes viral gene expression and replication of polyomavirus SV40: acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29447282). (Microbial infection) Promotes viral gene expression and virion production of kaposis sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells) (PubMed:29659627). Acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29659627).

关联

100 项与 YTHDF2 相关的临床结果

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100 项与 YTHDF2 相关的转化医学

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0 项与 YTHDF2 相关的专利（医药）

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646

项与 YTHDF2 相关的文献（医药）

2024-02-22·Molecular and cellular biochemistry

METTL3-mediated m6A modification of NORAD inhibits the ferroptosis of vascular smooth muscle cells to attenuate the aortic dissection progression in an YTHDF2-dependent manner.

Article

作者: Mingfang Liao ; Sili Zou ; Jianjin Wu ; Jun Bai ; Yandong Liu ; Kangkang Zhi ; Lefeng Qu

Ferroptosis of vascular smooth muscle cells (VSMCs) is related to the incidence of aortic dissection (AD). Long non-coding RNA (lncRNA) NORAD plays a crucial role in the progression of various diseases. The present study aimed to investigate the effects of NORAD on the ferroptosis of VSMCs and the molecular mechanisms. The expression of NORAD, HUR, and GPX4 was detected using quantitative real-time PCR (qPCR) or western blot. Ferroptosis was evaluated by detecting lactate dehydrogenase (LDH) activity, lipid reactive oxygen species (ROS), malonaldehyde (MDA) content, L-Glutathione (GSH) level, Fe²⁺ content, and ferroptosis-related protein levels. The molecular mechanism was assessed using RNA pull-down, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assay. The histology of aortic tissues was assessed using H&E, elastic Verhoeff-Van Gieson (EVG), and Masson staining assays. The data indicated that NORAD was downregulated in patients with AD and AngII-treated VSMCs. Overexpression of NORAD promoted VSMC growth and inhibited the ferroptosis induced by AngII. Mechanistically, NORAD interacted with HUR, which promoted GPX4 mRNA stability and elevated GPX4 levels. Knockdown of GPX4 abrogated the effects of NORAD on cell growth and ferroptosis of AngII-treated VSMCs. Moreover, METTL3 promoted m6A methylation of NORAD in an YTHDF2-dependent manner. In addition, NORAD attenuated AAD symptoms, incidence, histopathology, inflammation, and ferroptosis in AAD mice. In conclusion, METTL3-mediated NORAD inhibited ferroptosis of VSMCs via the HUR/GPX4 axis and decelerated AAD progression, suggesting that NORAD may be an AD therapeutic target.

2024-02-21·Molecular carcinogenesis

FTO promotes the progression of retinoblastoma through YTHDF2-dependent N6-methyladenosine modification in E2F3.

Article

作者: Weiwei Xie ; Yongqing Shao ; Qingyun Bo ; Zhen Li ; Qihua Yu ; Layi Wang ; Guohai Wu

Early treatment of retinoblastoma (RB) has significantly improved clinical outcomes. N6-methyladenosine (m6A) methylation is crucial for cancer progression. Thus, we investigated the role of FTO-dependent demethylation in RB and its underlying mechanisms. The biological behavior of RB cells was analyzed using cell counting kit-8, colony formation analysis, transwell assay, flow cytometry, and western blot analysis. m6A modification was evaluated using methylated RNA immunoprecipitation and dual-luciferase reporter assays, and E2F3 stability was assessed using Actinomycin D. The roles of FTO and E2F3 were also elucidated in vivo. These results indicated that FTO was highly expressed in RB cells with low m6A levels. FTO knockdown inhibited RB cell growth, migration, invasion, and epithelial-mesenchymal transition and arrested the cell cycle at the G0/G1 phase. Mechanistically, FTO interference promoted m6A methylation of E2F3, which was recognized by YTHDF2, thereby reducing mRNA stability. E2F3 overexpression partially rescued the effects of FTO knockdown on biological behavior. Moreover, FTO knockdown reduced tumor weight, tumor volume, ki67 expression, and tumor cell infiltration by mediating E2F3. Taken together, FTO silencing inhibited the malignant processes of RB by suppressing E2F3 in an m6A-YTHD2-dependent manner. These findings suggest that FTO is a novel therapeutic target for RB.

2024-02-16·International journal of molecular sciences

YTHDF2 as a Mediator in BDNF-Induced Proliferation of Porcine Follicular Granulosa Cells.

Article

作者: Kening Liu ; Xu Zhou ; Chunjin Li ; Caomeihui Shen ; Guitian He ; Tong Chen ; Maosheng Cao ; Xue Chen ; Boqi Zhang ; Lu Chen

In female mammals, the proliferation and apoptosis of granulosa cells (GCs) are critical in determining the fate of follicles and are influenced by various factors, including brain-derived neurotrophic factor (BDNF). Previous research has shown that BDNF primarily regulates GC proliferation through the PI3K/AKT, NF-kB, and CREB tumour pathways; however, the role of other molecular mechanisms in mediating BDNF-induced GC proliferation remains unclear. In this study, we investigated the involvement of the m⁶A reader YTH domain-containing family member 2 (YTHDF2) in BDNF-stimulated GC proliferation and its underlying mechanism. GCs were cultured in DMEM medium supplemented with varying BDNF concentrations (0, 10, 30, 75, and 150 ng/mL) for 24 h. The viability, number, and cell cycle of GCs were assessed using the CCK-8 assay, cell counting, and flow cytometry, respectively. Further exploration into YTHDF2's role in BDNF-stimulated GC proliferation was conducted using RT-qPCR, Western blotting, and sequencing. Our findings indicate that YTHDF2 mediates the effect of BDNF on GC proliferation. Additionally, this study suggests for the first time that BDNF promotes YTHDF2 expression by increasing the phosphorylation level of the ERK1/2 signalling pathway. This study offers a new perspective and foundation for further elucidating the mechanism by which BDNF regulates GC proliferation.

项与 YTHDF2 相关的新闻（医药）

2023-08-02

·生物谷

Cancer Res：深圳大学吴松团队发现膀胱癌免疫疗法重要靶点

该工作首次明确了YTHDF2在膀胱癌中促进肿瘤从NMIBC进展至MIBC，揭示了YTHDF2识别并结合m6A修饰的RIG-I mRNA，并加速其在膀胱癌细胞中的衰变，从而抑制肿瘤进展过程中RIG-I介膀胱尿路上皮癌（BLCA）是泌尿系统最常见的恶性疾病，复发率高，且易进展为更高级别的肌肉浸润性膀胱癌（MIBC）。目前对于BLCA进展的分子机制还不十分清楚，这使得针对BLCA的靶向治疗方案匮乏，现有方法多是借鉴其他肿瘤的治疗经验。BLCA患者往往接受膀胱内卡介苗（BCG）治疗，作为经尿道浅表肿瘤切除术后根除残留肿瘤细胞的标准临床策略。然而，相当多的患者在治疗开始时对BCG治疗没有反应或在治疗过程中产生耐药性，这也是临床面临的痛点。 RNA甲基化是一类新型表观遗传修饰，最近的研究强调了RNA甲基化修饰m6A在许多疾病（包括膀胱癌）中的异常调节，然而，m6A阅读器YTHDF2是否调控膀胱癌进展，以及是否与BCG治疗响应相关仍有待研究。近日，深圳大学吴松教授，中山大学崔隽教授和广州实验室Jean Paul Thiery教授课题组合作，在 Cancer Research 期刊发表了题为：The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response 的研究论文。该研究首次报道了m6A阅读器YTHDF2可以促进膀胱尿路上皮癌（BLCA）从非基层浸润型膀胱癌（NMIBC）进展为肌肉浸润性膀胱癌（MIBC），并揭示了YTHDF2以m6A依赖的方式调控RIG-I mRNA降解，从而抑制肿瘤进展过程中RIG-I信号通路介导的抗肿瘤免疫反应的新机制。该研究还强调了靶向YTHDF2可能有益于卡介苗（BCG）免疫疗法。该研究通过公共数据库分析、免疫组化和组织芯片分析发现YTHDF2在膀胱肿瘤样本中会呈现RNA和蛋白质水平的上调，并且YTHDF2的高表达与FGFR3突变相关，表明YTHDF2可能在携带突变FGFR3的患者中发挥重要作用。从NMIBC进展到MIBC是这些患者的主要问题。数据集的分析也进一步证实与NMIBC肿瘤相比，YTHDF2在MIBC中的表达更高，并且与原发性肿瘤相比，在复发性和进展性肿瘤中的表达更高。基于TMA的IHC染色对BLCA样本中的YTHDF2进行总生存分析发现，YTHDF2表达较低的患者具有更好的预后，表现为较长的总生存。这些数据都表明YTHDF2可能有助于BLCA进展。那么YTHDF2如何调控BLCA进展呢？作者首先明确了YTHDF2分别在体外和体内促进BLCA细胞的增殖和肿瘤生长。综合RNA测序和m6A测序分析表明RIG-I是YTHDF2的下游靶标。分子和细胞实验表明，YTHDF2与DDX58 mRNA的编码序列结合并以m6A依赖性方式介导其降解。并且，RIG-I的敲低抑制细胞凋亡，促进BLCA细胞的增殖，并促进肿瘤的进展。此外，作者通过小鼠原位膀胱癌模型发现了Ythdf2 KO细胞形成的肿瘤更小，小鼠生存更久，表现出更高水平的先天免疫反应，并促进CD8+T淋巴细胞的募集。图1：YTHDF2调控BLCA抗肿瘤免疫的分子机制已有报道表明，BCG治疗需要T细胞。因此，作者接下来试图确定YTHDF2缺乏是否可以增强BCG治疗的疗效。C57BL/6小鼠被植入对照或Ythdf2 KO MB49细胞，并每周接受3次BCG膀胱内治疗。作者观察到与对照小鼠相比，接种Ythdf2 KO细胞的小鼠肿瘤更小，存活率延长。此外，BCG处理导致CD8+细胞的强烈浸润，而Ythdf2 KO联合BCG治疗更进一步增强了CD8+细胞募集。这表明，YTHDF2缺失通过增加肿瘤微环境和尿路上皮中的CD8+T细胞浸润而有益于BCG免疫治疗疗效。因此，靶向YTHDF2的方案联合临床上BCG免疫疗法对FGFR3突变YTHDF2高表达患者来说，可能会是一种新的选择。图2：敲低YTHDF2有益于BCG疗效的机制该工作首次明确了YTHDF2在膀胱癌中促进肿瘤从NMIBC进展至MIBC，揭示了YTHDF2识别并结合m6A修饰的RIG-I mRNA，并加速其在膀胱癌细胞中的衰变，从而抑制肿瘤进展过程中RIG-I介导的免疫反应的分子机制。该工作强调了RIG-I信号在 BLCA进展中的作用，提示了靶向YTHDF2可增加了免疫细胞向瘤床和尿路上皮的浸润，从而增强BCG免疫治疗的疗效。该工作将有助于BCG免疫疗法联合方案开发的思考。张磊博士、李宇清博士和周伶俐博士为论文共同第一作者。深圳大学吴松教授为文章的通讯作者。中山大学崔隽教授和广州实验室Jean Paul Thiery教授为该工作提供了重要帮助。

信使RNA免疫疗法临床结果

2023-07-28

·生物谷

南京医科大学附属苏州医院的研究者们指出M6A修饰的LINC00839具有抗肿瘤进展和抗辐射作用

胶质母细胞瘤(GBM)是成人最具侵袭性和最常见的原发脑肿瘤。尽管采取了综合治疗，包括最大限度的手术切除、放疗和化疗，但GBM患者的预后仍然很差。胶质母细胞瘤(GBM)是成人最具侵袭性和最常见的原发脑肿瘤。尽管采取了综合治疗，包括最大限度的手术切除、放疗和化疗，但GBM患者的预后仍然很差。胶质瘤干细胞(GSCs)具有自我更新能力，呈金字塔状，对放化疗耐药，被认为是GBM复发的种子。先前的结果表明，GSCs通过向肿瘤细胞运送外体miR-30b-3p来促进GBM对TMZ的耐药性。研究还确定了一些GSC特异的分子靶点，如骨髓和X-连锁(BMX)信号转导和转录激活因子3(STAT3)，与放射治疗耐药有关。然而，克服放疗抵抗仍是脑胶质瘤临床治疗的难点。因此，需要发现更多的分子来开发新的治疗方法。图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-05933-7 近日，来自南京医科大学附属苏州医院的研究者们在Cell Death and Disease杂志上发表了题为“METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/β-catenin signaling”的文章，该研究揭示了METTL3介导的M6A修饰LINC00839通过激活Wnt/β-catenin信号维持胶质瘤干细胞和辐射抗性。长非编码RNA(LncRNAs)参与了胶质瘤的发生和发展。胶质瘤干细胞(GSCs)是肿瘤发生、维持和治疗耐药所必需的。然而，LncRNAs在GSCs中的生物学功能和潜在机制仍然知之甚少。在此，研究者发现LINC00839在GSC中高表达。高水平的LINC00839与GBM进展和辐射抵抗有关。 METTL3介导的M6A修饰LINC00839以YTHDF2依赖的方式增强其表达。在机制上，LINC00839作为支架促进c-Src介导的β-连环蛋白的磷酸化，从而诱导WNT/β-连环蛋白的激活。联合应用Wnt/β-catenin信号通路的抑制剂塞来昔布可显著提高GSC对辐射的敏感性。综上所述，我们的结果表明，经METTL3介导的m6A修饰的LINC00839通过激活Wnt/β-catenin信号通路而发挥肿瘤进展和辐射抵抗作用。 LINC00839与GSC中的β-连环蛋白相互作用图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-05933-7 综上所述，研究者阐明了LINC00839在GSCs中的功能，并提出了METTL3/YTHDF2以m6A依赖的方式维持LINC00839表达的分子机制模型。稳定的LINC00839作为一个支架，指导c-Src与β-连环蛋白的结合和磷酸化，从而促进Wnt信号的激活。联合应用Wnt/β-Catenin信号抑制剂塞来昔布增敏放射治疗脑瘤的动物研究。（生物谷 Bioon.com）参考文献 Jianxing Yin et al. METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/β-catenin signaling. Cell Death Dis. 2023 Jul 12;14(7):417. doi: 10.1038/s41419-023-05933-7.

放射疗法临床研究

2023-05-29

·生物谷

Cancer Cell：何川/罗成等发现抑制YTHDF2可增强放疗的抗肿瘤疗效

目前，50-60%的癌症患者采用放射治疗（Radiation Therapy，RT），尽管技术和治疗方法不断改进，但很多患者由于耐药或转移而导致治疗失败。放射增敏治疗策略一般集中在抑制DNA修复或增加目前，50-60%的癌症患者采用放射治疗（Radiation Therapy，RT），尽管技术和治疗方法不断改进，但很多患者由于耐药或转移而导致治疗失败。放射增敏治疗策略一般集中在抑制DNA修复或增加DNA损伤上，其中免疫环境对治愈性至关重要。临床前数据表明，电离辐射（Ionizing Radiation，IR）单独或联合免疫检查点阻断具有免疫刺激作用。基于此，越来越多的临床试验启动免疫检查点阻断与IR联合疗法。然而，目前治疗效果有限，放疗联合免疫检查点疗法的协同作用机制及两者之间的相互关系仍需进一步探索。 N6-甲基腺苷（m6A）是真核生物中最常见的mRNA的修饰，主要调控mRNA的稳定性和翻译效率。m6A主要由RNA甲基转移酶（writer）—METTL3/METTL14、RNA去甲基化酶（eraser）—FTO和ALKBH5动态调控，随后由“阅读子”（reader）—YTHDF1/2/3和YTHDC1/2识别调节RNA代谢。研究表明，YTHDF2参与调控多种生物学过程，包括细胞周期进程，应激反应等，并与多种肿瘤生长有关。然而，YTHDF2在免疫细胞中的调控作用，尤其是在放疗和免疫治疗中的作用尚未被深入探讨。 2023年5月25日，芝加哥大学 Ralph Weichselbaum 教授、何川教授、Hua Laura Liang 教授与中国科学院上海药物研究所罗成研究员等在 Cancer Cell 期刊发表了题为：YTHDF2 inhibition potentiates radiotherapy anti-tumor efficacy 的研究论文。该研究发现，YTHDF2可作为放疗和放疗/免疫联合疗法的潜在靶点，提出了通过抑制YTHDF2来增强临床放射治疗效果的新策略。该研究发现，电离辐射（IR）在小鼠模型和人体内均可诱导免疫抑制性MDSC扩增和YTHDF2表达。IR介导放疗后，表达YTHDF2的MDSC群体增加，这与放疗后的转移进展有关。因此，研究人员猜想YTHDF2的增加是影响放疗效果的原因。于是，研究人员通过构建Ythdf2敲除小鼠模型，发现IR后，Ythdf2的缺失可改变MDSC分化，抑制MDSC向肿瘤转运，并减弱其抑制功能，增强了抗肿瘤免疫，从而增强了局部肿瘤IR的功效。进一步，研究人员发现，IR诱导的YTHDF2表达上调主要依赖于NF-κB/RELA信号通路。反过来，上调的YTHDF2通过直接结合并降解编码NF-κB信号负调控因子（Adrb2、Metrnl和Smpdl3b）的转录本，导致NF-κB活化，从而形成 IR-YTHDF2-NF-κB回路。这些都表明，可以通过抑制YTHDF2来提高抗肿瘤免疫和放疗效果，其有望成为临床放射治疗的新策略。为了进一步证明YTHDF2是潜在的改善放疗和RT/免疫联合疗法的靶点，研究人员通过靶向YTHDF2开展化学干预研究。基于建立的化合物高通量筛选方法，开展了小分子抑制剂的筛选并获得了YTHDF2的活性化合物DC-Y13。通过结构改造获得了化合物DC-Y13-27，其可以在体外直接结YTHDF2蛋白并抑制其与m6A-RNA的结合。此外，DC-Y13-27在小鼠上与敲除YTHDF2类似，不仅可有效提高的IR疗效，而且提高了IR与PD-L1抗体联合治疗的抗肿瘤效果。抑制YTHDF2克服了MDSC诱导的免疫抑制，不仅可以改善局部肿瘤治疗效果，还可以抑制肿瘤转移。