Ythdf3, an N6-methyladenosine (m6A) reader protein, is crucial in regulating the metabolism of m6A-modified mRNAs in the cytoplasm. It is involved in various biological processes such as translation, mRNA decay, and autophagy, and is associated with multiple disease-related pathways, especially cancer-related ones. Genetic models, like gene-knockout (KO) mouse models, can be valuable for further exploring its functions [4].

In breast cancer, Ythdf3 overexpression correlates with brain metastases. It promotes cancer cell interactions with brain-related cells, blood-brain barrier extravasation, angiogenesis, etc., by enhancing the translation of m6A-enriched transcripts for genes like ST6GALNAC5, GJA1, and EGFR [1]. In pancreatic cancer, ZDHHC20-mediated S-palmitoylation of Ythdf3 stabilizes MYC mRNA to promote cancer progression. Inhibition of Ythdf3 palmitoylation downregulates MYC expression and suppresses the progression of KRAS mutant pancreatic cancer [2]. For autophagy, Ythdf3 is essential for autophagy induction. It promotes autophagy by recognizing m6A modification sites around the stop codon of FOXO3 mRNA and recruiting translation-related factors to up-regulate FOXO3 translation [3,7]. In liver fibrosis, Ythdf3-mediated PRDX3 translation alleviates liver fibrosis [5]. In glioblastoma, Ythdf3 modulates the EGFR/ATK/ERK/p21 signaling axis to promote cancer progression and osimertinib resistance [6]. In melanoma, Ythdf3 regulates metastasis via its target LOXL3 [8]. In castration-resistant prostate cancer, Ythdf3 regulates the degradation and stability of m6A-enriched transcripts to facilitate cancer progression, and melatonin can inhibit Ythdf3-related activities [9].

In conclusion, Ythdf3 plays essential roles in multiple biological processes, especially in cancer-related events, as revealed through various functional studies. Model-based research, such as KO/CKO mouse models (although not explicitly detailed in all references), could potentially further clarify its functions in these specific disease areas, providing insights for targeted therapeutic strategies.

References:

1. Chang, Guoqiang, Shi, Lei, Ye, Youqiong, He, Chuan, Huang, Suyun. 2020. YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis. In Cancer cell, 38, 857-871.e7. doi:10.1016/j.ccell.2020.10.004. https://pubmed.ncbi.nlm.nih.gov/33125861/

2. Zhang, Huan, Sun, Yan, Wang, Zhaokai, Jiang, Ke, Jin, Xin. 2024. ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression. In Nature communications, 15, 4642. doi:10.1038/s41467-024-49105-3. https://pubmed.ncbi.nlm.nih.gov/38821916/

3. Hao, WeiChao, Dian, MeiJuan, Zhou, Ying, Sun, Yan, Xiao, Dong. 2022. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA. In Nature communications, 13, 5845. doi:10.1038/s41467-022-32963-0. https://pubmed.ncbi.nlm.nih.gov/36195598/

4. Shi, Hailing, Wang, Xiao, Lu, Zhike, Liu, Chang, He, Chuan. 2017. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. In Cell research, 27, 315-328. doi:10.1038/cr.2017.15. https://pubmed.ncbi.nlm.nih.gov/28106072/

5. Sun, Ruimin, Tian, Xinyao, Li, Yang, Zheng, Shusen, Yao, Jihong. 2022. The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis. In Redox biology, 54, 102378. doi:10.1016/j.redox.2022.102378. https://pubmed.ncbi.nlm.nih.gov/35779442/

6. Lee, Hsun-Hua, Hsieh, Ching-Chuan, Chang, Cheng-Chih, Liao, Wan-Ting, Chi, Hsiang-Cheng. . YTHDF3 Modulates EGFR/ATK/ERK/p21 Signaling Axis to Promote Cancer Progression and Osimertinib Resistance of Glioblastoma Cells. In Anticancer research, 43, 5485-5498. doi:10.21873/anticanres.16751. https://pubmed.ncbi.nlm.nih.gov/38030188/

7. Hao, WeiChao, Dian, MeiJuan, Wang, JiaHong, Sun, Yan, Xiao, Dong. 2022. Epitranscriptomic turbo for autophagy boost: m6A reader YTHDF3. In Autophagy, 19, 1882-1884. doi:10.1080/15548627.2022.2146890. https://pubmed.ncbi.nlm.nih.gov/36374269/

8. Shi, Hao-Ze, Xiong, Jing-Shu, Gan, Lu, Sun, Jian-Fang, Chen, Hao. . N6-methyladenosine reader YTHDF3 regulates melanoma metastasis via its 'executor'LOXL3. In Clinical and translational medicine, 12, e1075. doi:10.1002/ctm2.1075. https://pubmed.ncbi.nlm.nih.gov/36324258/

9. Duan, Juanjuan, Fan, Daogui, Chen, Pingping, Yu, Wenfeng, Zhang, Qifang. . YTHDF3 Regulates the Degradation and Stability of m6A-Enriched Transcripts to Facilitate the Progression of Castration-Resistant Prostate Cancer. In Journal of pineal research, 76, e13003. doi:10.1111/jpi.13003. https://pubmed.ncbi.nlm.nih.gov/39143673/