YTH结构域N6-甲基腺嘌呤RNA结合蛋白2的生物学作用及其在肿瘤中应用的研究进展

doi:10.3969/j.issn.1006-5725.2025.04.023

Abstract

Abstract:

YTHDF2 is a key m6A RNA modification "reader" that plays a crucial role in cell biological processes and tumor development. This review deeply explores the biological role of YTHDF2 and the advances in its application in tumors. The YTHDF2 structures are divided into mRNA procsomes and YTH domains， which recognize and bind m6A modified RNA molecules. It plays a biological role by promoting mRNA degradation， regulating cell signaling pathways and metabolism， and can regulate macrophage function and maintain an immunosuppressive state in the tumor microenvironment. YTHDF2 has the potential to serve as diagnostic markers， therapeutic targets and prognostic evaluation biomarkers in different tumors， but currently relevant studies are insufficient in sample size， molecular mechanism and clinical application. In the future， research can be conducted on comprehensive clinical research， in-depth analysis of molecular mechanisms， and research and development of optimized treatment strategies.

Key words: YTHDF2, m6A modification, biological role, tumor, diagnostic marker, therapeutic target, prognostic evaluation

CLC Number:

R73-31

Dengxinjie SHI,Hongjin SHI,Nan ZHANG,Shi FU,Qun WANG,Haonan DONG,Jiansong WANG,Haidan LI,Haifeng. WANG. The biological role of YTHDF2 and its application in tumors[J]. The Journal of Practical Medicine, 2025, 41(4): 615-620.

Figures/Tables 1

References 41

1	CHEN Y， LIN Y， SHU Y， et al. Interaction between N6-methyladenosine （m6A） modification and noncoding RNAs in cancer［J］. Mol Cancer， 2020， 19（1 ）： 94. doi:10.1186/s12943-020-01207-4 doi: 10.1186/s12943-020-01207-4
2	DU H， ZHAO Y， HE J， et al. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4⁃NOT deadenylase complex［J］. Nat Commun， 2016， 7： 12626. doi:10.1038/ncomms12626 doi: 10.1038/ncomms12626
3	CHEN X， ZHOU X， WANG X. m6A binding protein YTHDF2 in cancer［J］. Exp Hematol Oncol， 2022， 11（1）： 21. doi:10.1186/s40164-022-00269-y doi: 10.1186/s40164-022-00269-y
4	CARDELLI M， MARCHEGIANI F， CAVALLONE L， et al. A Polymorphism of the YTHDF2 Gene （1p35） Located in an Alu-Rich Genomic Domain Is Associated With Human Longevity［J］. J Gerontol A Biol Sci Med Sci， 2006， 61（6）： 547-556. doi:10.1093/gerona/61.6.547 doi: 10.1093/gerona/61.6.547
5	WANG J Y， LU A Q. The biological function of m6A reader YTHDF2 and its role in human disease［J］. Cancer Cell Int， 2021， 21： 109. doi:10.1186/s12935-021-01807-0 doi: 10.1186/s12935-021-01807-0
6	JIN D， GUO J， WU Y， et al. m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC［J］. Mol Cancer， 2020， 19（1）： 40. doi:10.1186/s12943-020-01161-1 doi: 10.1186/s12943-020-01161-1
7	EINSTEIN J M， PERELIS M， CHAIM I A， et al. Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer［J］. Mol Cell， 2021， 81（15）： 3048-3064.e9. doi:10.1016/j.molcel.2021.06.014 doi: 10.1016/j.molcel.2021.06.014
8	LI J， XIE H， YING Y， et al. YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer［J］. Mol Cancer， 2020， 19（1）： 152. doi:10.1186/s12943-020-01267-6 doi: 10.1186/s12943-020-01267-6
9	CHEN Z， SHAO Y L， WANG L L， et al. YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t（8；21） AML［J］. Oncogene， 2021， 40（22）： 3786-3798. doi:10.1038/s41388-021-01818-1 doi: 10.1038/s41388-021-01818-1
10	YAN J， HUANG X， ZHANG X， et al. LncRNA LINC00470 promotes the degradation of PTEN mRNA to facilitate malignant behavior in gastric cancer cells［J］. Biochem Biophys Res Commun， 2020， 521（4）： 887-893. doi:10.1016/j.bbrc.2019.11.016 doi: 10.1016/j.bbrc.2019.11.016
11	YANG X， ZHANG S， HE C， et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST［J］. Mol Cancer， 2020，19（1）：46. doi:10.1186/s12943-020-1146-4 doi: 10.1186/s12943-020-1146-4
12	HOU J， ZHANG H， LIU J， et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma［J］. Mol Cancer， 2019， 18（1）： 163. doi:10.1186/s12943-019-1082-3 doi: 10.1186/s12943-019-1082-3
13	CHEN J， SUN Y， XU X， et al. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells［J］. Cell Cycle， 2017， 16（23）： 2259-2271. doi:10.1080/15384101.2017.1380125 doi: 10.1080/15384101.2017.1380125
14	WANG X， ZHANG J， WANG Y. Long noncoding RNA GAS5-AS1 suppresses growth and metastasis of cervical cancer by increasing GAS5 stability［J］. Am J Transl Res， 2019， 11（8）： 4909-4921.
15	DIXIT D， PRAGER B C， GIMPLE R C， et al. The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells［J］. Cancer Discov， 2021， 11（2）： 480-499. doi:10.1158/2159-8290.cd-20-0331 doi: 10.1158/2159-8290.cd-20-0331
16	YU J， CHAI P， XIE M， et al. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma［J］. Genome Biol， 2021， 22（1）： 85. doi:10.1186/s13059-021-02308-z doi: 10.1186/s13059-021-02308-z
17	WANG X， LU Z， GOMEZ A， et al. N6-methyladenosine-dependent regulation of messenger RNA stability［J］. Nature， 2014， 505（7481）： 117-120. doi:10.1038/nature12730 doi: 10.1038/nature12730
18	ZHU T， ROUNDTREE I A， WANG P， et al. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine［J］. Cell Res， 2014， 24（12）： 1493-1496. doi:10.1038/cr.2014.152 doi: 10.1038/cr.2014.152
19	PARK O H， HA H， LEE Y， et al. Endoribonucleolytic Cleavage of m6A-Containing RNAs by RNase P/MRP Complex［J］. Mol Cell， 2019， 74（3）： 494-507.e8. doi:10.1016/j.molcel.2019.02.034 doi: 10.1016/j.molcel.2019.02.034
20	FEI Q， ZOU Z， ROUNDTREE I A， et al. YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators［J］. PLoS Biol， 2020， 18（4）： e3000664. doi:10.1371/journal.pbio.3000664 doi: 10.1371/journal.pbio.3000664
21	LI H， ZHANG N， JIAO X， et al. Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3β［J］. Clin Transl Med， 2021， 11（10）： e602. doi:10.1002/ctm2.602 doi: 10.1002/ctm2.602
22	WANG W， SHAO F， YANG X， et al. METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N6-methyladenosine-dependent YTHDF binding［J］. Nat Commun， 2021， 12（1）： 3803. doi:10.1038/s41467-021-24860-9 doi: 10.1038/s41467-021-24860-9
23	KORINEK V， BARKER N， MORIN P J， et al. Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC-/- Colon Carcinoma［J］. Science， 1997， 275（5307）： 1784-1787. doi:10.1126/science.275.5307.1784 doi: 10.1126/science.275.5307.1784
24	YU P， XU T， MA W， et al. PRMT6-mediated transcriptional activation of ythdf2 promotes glioblastoma migration， invasion， and emt via the wnt-β-catenin pathway［J］. J Exp Clin Cancer Res， 2024， 43（1）： 116. doi:10.1186/s13046-024-03038-3 doi: 10.1186/s13046-024-03038-3
25	LIU R， LI W， TAO B， et al. Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance［J］. Nat Commun， 2019， 10（1）： 991. doi:10.1038/s41467-019-08921-8 doi: 10.1038/s41467-019-08921-8
26	SHENG H， LI Z， SU S， et al. YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation［J］. Carcinogenesis， 2020， 41（5）： 541-550. doi:10.1093/carcin/bgz152 doi: 10.1093/carcin/bgz152
27	ITALIANI P， BORASCHI D. From Monocytes to M1/M2 Macrophages： Phenotypical vs. Functional Differentiation［J］. Front Immunol， 2014， 5：514. doi:10.3389/fimmu.2014.00514 doi: 10.3389/fimmu.2014.00514
28	MA S， SUN B， DUAN S， et al. YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8⁺ T cells［J］. Nat Immunol， 2023， 24（2）： 255-266. doi:10.1038/s41590-022-01398-6 doi: 10.1038/s41590-022-01398-6
29	ZHANG L， DOU X， ZHENG Z， et al. YTHDF2/m6 A/NF-κB axis controls anti-tumor immunity by regulating intratumoral Tregs［J］. EMBO J， 2023， 42（15）： e113126. doi:10.15252/embj.2022113126 doi: 10.15252/embj.2022113126
30	GRINBERG-BLEYER Y， CARON R， SEELEY J J， et al. The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function［J］. J Immunol， 2018， 200（7）： 2362-2371. doi:10.4049/jimmunol.1800042 doi: 10.4049/jimmunol.1800042
31	BETZLER A C， THEODORAKI M N， SCHULER P J， et al. NF-κB and Its Role in Checkpoint Control［J］. Int J Mol Sci， 2020， 21（11）： 3949. doi:10.3390/ijms21113949 doi: 10.3390/ijms21113949
32	张娅威，施鸿金，付什，等. TIGIT的生物学作用及其在膀胱癌中应用的研究进展［J］. 实用医学杂志， 2024，40（12）： 1762-1766.
33	ZHANG L， LI Y， ZHOU L， et al. The m6A Reader YTHDF2 Promotes Bladder Cancer Progression by Suppressing RIG-I–Mediated Immune Response［J］. Cancer Res， 2023， 83（11）： 1834-1850. doi:10.1158/0008-5472.can-22-2485 doi: 10.1158/0008-5472.can-22-2485
34	王月帆，葛春梅，尹昊瓒，等. m6A甲基化修饰识别蛋白YTHDF2在肝癌组织中的表达及临床意义［J］. 现代生物医学进展， 2021， 21（9）： 1601-1606.
35	胡宽，姚磊，李娟妮，等. YTH基因家族在肝癌中的表达和预后价值［J］. 中国普通外科杂志， 2021， 30（7）： 836-846.
36	马琰迪，卢香云，何尚峰，等. m6A甲基化修饰结合蛋白YTHDF2在食管癌组织中的表达及其对食管癌细胞增殖和迁移的影响［J］. 吉林大学学报（医学版）， 2022， 48（4）： 962-970.
37	LIU W， LIU C， YOU J， et al. Pan-cancer analysis identifies YTHDF2 as an immunotherapeutic and prognostic biomarker［J］. Front Cell Dev Biol， 2022， 10： 954214. doi:10.3389/fcell.2022.954214 doi: 10.3389/fcell.2022.954214
38	孟肖娜，孙旭，刘怀民. 免疫检查点抑制剂相关结肠炎的研究进展［J］. 实用医学杂志， 2024，40（9）： 1314-1319.
39	HUANG C S， ZHU Y Q， XU Q C， et al. YTHDF2 promotes intrahepatic cholangiocarcinoma progression and desensitises cisplatin treatment by increasing CDKN1B mRNA degradation［J］. Clin Transl Med， 2022， 12（6）： e848. doi:10.1002/ctm2.848 doi: 10.1002/ctm2.848
40	WANG L， DOU X， CHEN S， et al. YTHDF2 inhibition potentiates radiotherapy antitumor efficacy［J］. Cancer Cell， 2023， 41（7）： 1294-1308.e8. doi:10.1016/j.ccell.2023.04.019 doi: 10.1016/j.ccell.2023.04.019
41	SU G， LIU T， HAN X， et al. YTHDF2 is a Potential Biomarker and Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma［J］. Front Pharmacol， 2021， 12： 709548. doi:10.3389/fphar.2021.709548 doi: 10.3389/fphar.2021.709548

肿瘤类型	YTHDF2表达情况	在肿瘤进展中的作用	分子机制	临床意义	参考文献
胃癌（GC）	上调	致癌基因	降解PTEN mRNA促进增殖、侵袭和迁移	与不良预后相关	［10］
结直肠癌（CRC）	下调	抑癌基因	抑制细胞生长和血管生成	与较好预后相关	［11］
肝细胞癌（HCC）	下调	抑癌基因	制细胞生长和血管生成	与延长生存相关	［12］
胰腺癌（PC）	上调	致癌基因	靶向PIK3CB促进增殖和EMT	与不良预后相关	［13］
非小细胞肺癌（NSCLC）	上调	致癌基因	促进增殖、侵袭和免疫逃逸	与不良预后相关	［6］
急性髓性白血病（AML）	上调	致癌基因	缩短m6A转录本半衰期，增强白血病干细胞功能	靶向YTHDF2可能增强造血干细胞扩增	［9］
前列腺癌（PCa）	上调	致癌基因	促进增殖、迁移和集落形成	与高肿瘤分级和不良预后相关	［8］
三阴性乳腺癌（TNBC）	上调	致癌基因	促进MYC驱动的TNBC细胞增殖和抑制凋亡	与不良预后相关	［7］
宫颈癌（CC）	下调	抑癌基因	增加GAS5表达和稳定性，抑制增殖和迁移	与较好预后相关	［14］
胶质母细胞瘤（GBM）	上调	致癌基因	维持癌基因表达，促进侵袭性生长	与不良预后相关	［15］
黑色素瘤	下调	抑癌基因	去甲基化并不稳定化致癌性mRNA	与较好预后相关	［16］

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The biological role of YTHDF2 and its application in tumors

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