Ythdf2, the YT521-B homology domain 2, is an N6-methyladenosine (m6A) reader. m6A modification is a prevalent post-transcriptional RNA modification, and Ythdf2 usually destabilizes m6A-modified mRNA, thus regulating gene expression at the post-transcriptional level. It is involved in various biological processes and associated with multiple signaling pathways such as NF-κB, STAT-related pathways, which are crucial for cell differentiation, immune response, and tumorigenesis [1,2,3,4,5,6,7,8,9,10]. Genetic models, especially KO/CKO mouse models, have been instrumental in studying Ythdf2's functions.

In KO mouse models, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering myeloid-derived suppressor cell (MDSC) differentiation, inhibiting MDSC infiltration and suppressive function [1]. In tumor-associated macrophages (TAMs), Ythdf2 deficiency suppresses tumor growth by reprogramming TAMs toward an antitumoral phenotype and enhancing CD8+ T cell-mediated antitumor immunity [2]. In MYC-driven breast cancer, disrupting Ythdf2-dependent mRNA degradation triggers apoptosis in triple-negative breast cancer cells and tumors [5]. In glioblastoma, Ythdf2 is required for cell proliferation, invasion, and tumorigenesis, and its overexpression correlates with poor patient prognosis [6]. In hepatocellular carcinoma, decreased ubiquitination levels of Ythdf2 contribute to its upregulation, promoting proliferation and sorafenib resistance [7]. In bladder cancer, Ythdf2 promotes tumor progression by suppressing RIG-I-mediated immune response, and its deficiency enhances Bacillus Calmette-Guérin immunotherapy [9]. In NK cells, Ythdf2 deficiency impairs antitumor and antiviral activity, as it maintains NK cell homeostasis, terminal maturation, effector function, and is involved in IL-15-mediated survival and proliferation [10].

In conclusion, Ythdf2, as an m6A reader, plays a vital role in regulating gene expression through mRNA destabilization. Model-based research, especially using KO/CKO mouse models, has revealed its diverse functions in tumorigenesis, immune response, and cell-specific homeostasis. These findings contribute to understanding the role of Ythdf2 in diseases such as cancer, highlighting its potential as a therapeutic target for improving cancer treatments, including radiotherapy and immunotherapy [1,2,5,6,7,8,9].

References:

1. Wang, Liangliang, Dou, Xiaoyang, Chen, Shijie, He, Chuan, Weichselbaum, Ralph R. 2023. YTHDF2 inhibition potentiates radiotherapy antitumor efficacy. In Cancer cell, 41, 1294-1308.e8. doi:10.1016/j.ccell.2023.04.019. https://pubmed.ncbi.nlm.nih.gov/37236197/

2. Ma, Shoubao, Sun, Baofa, Duan, Songqi, Caligiuri, Michael A, Yu, Jianhua. 2023. YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells. In Nature immunology, 24, 255-266. doi:10.1038/s41590-022-01398-6. https://pubmed.ncbi.nlm.nih.gov/36658237/

3. Yu, Jie, Chai, Peiwei, Xie, Minyue, Fan, Xianqun, Jia, Renbing. 2021. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. In Genome biology, 22, 85. doi:10.1186/s13059-021-02308-z. https://pubmed.ncbi.nlm.nih.gov/33726814/

4. Yang, Yang, Yan, Yu, Yin, Jiaxin, Gao, Qingzhu, Huang, Ailong. 2023. O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner. In Signal transduction and targeted therapy, 8, 63. doi:10.1038/s41392-023-01316-8. https://pubmed.ncbi.nlm.nih.gov/36765030/

5. Einstein, Jaclyn M, Perelis, Mark, Chaim, Isaac A, Westbrook, Thomas F, Yeo, Gene W. 2021. Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer. In Molecular cell, 81, 3048-3064.e9. doi:10.1016/j.molcel.2021.06.014. https://pubmed.ncbi.nlm.nih.gov/34216543/

6. Fang, Runping, Chen, Xin, Zhang, Sicong, He, Chuan, Huang, Suyun. 2021. EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. In Nature communications, 12, 177. doi:10.1038/s41467-020-20379-7. https://pubmed.ncbi.nlm.nih.gov/33420027/

7. Liao, Yuning, Liu, Yuan, Yu, Cuifu, Cai, Gengxi, Huang, Hongbiao. 2023. HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2302025. doi:10.1002/advs.202302025. https://pubmed.ncbi.nlm.nih.gov/37515378/

8. Xiao, Sai, Ma, Shoubao, Sun, Baofa, Caligiuri, Michael A, Yu, Jianhua. 2024. The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion. In Science immunology, 9, eadl2171. doi:10.1126/sciimmunol.adl2171. https://pubmed.ncbi.nlm.nih.gov/38820140/

9. Zhang, Lei, Li, Yuqing, Zhou, Lingli, Cui, Jun, Wu, Song. . The m6A Reader YTHDF2 Promotes Bladder Cancer Progression by Suppressing RIG-I-Mediated Immune Response. In Cancer research, 83, 1834-1850. doi:10.1158/0008-5472.CAN-22-2485. https://pubmed.ncbi.nlm.nih.gov/36939388/

10. Ma, Shoubao, Yan, Jiazhuo, Barr, Tasha, Caligiuri, Michael A, Yu, Jianhua. 2021. The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity. In The Journal of experimental medicine, 218, . doi:10.1084/jem.20210279. https://pubmed.ncbi.nlm.nih.gov/34160549/