YTHDF1, also known as YTH N6-methyladenosine RNA binding protein 1, is an m6A reader protein. It plays a crucial role in protein translation, tumor proliferation, metabolic reprogramming of various tumor cells, and immune evasion [4]. It is involved in multiple signaling pathways, regulating tumor-related metabolic processes [4]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In cancer research, KO of Ythdf1 in mouse models has revealed significant impacts. In colorectal cancer, genetic depletion of Ythdf1 augmented antitumor immunity in syngeneic tumors, while Ythdf1 knockin promoted an immunosuppressive tumor immune microenvironment (TIME), facilitating CRC progression. Mechanistically, YTHDF1 promoted p65 translation to upregulate CXCL1, increasing MDSC migration and antagonizing functional CD8+ T cells in TIME [1]. In NASH-HCC, Ythdf1 overexpression in hepatocytes drove tumorigenesis. Ythdf1 knockout synergized with anti-PD-1 treatment to suppress tumor growth, as Ythdf1 induced MDSC accumulation and CD8+ T-cell dysfunction through the EZH2-IL-6 axis [2]. In breast cancer, YTHDF1 knockdown sensitized cells to chemotherapeutic drugs, as YTHDF1 promoted cell growth, DNA damage repair, and chemoresistance in breast cancer cells [3].

In conclusion, YTHDF1 is a key regulator in tumor-related biological processes. Studies using KO/CKO mouse models have significantly advanced our understanding of its role in diseases like colorectal cancer, NASH-HCC, and breast cancer. These findings suggest YTHDF1 could be a potential therapeutic target for improving cancer immunotherapy and overcoming chemoresistance.

References:

1. Bao, Yi, Zhai, Jianning, Chen, Huarong, To, Ka Fai, Yu, Jun. 2023. Targeting m6A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer. In Gut, 72, 1497-1509. doi:10.1136/gutjnl-2022-328845. https://pubmed.ncbi.nlm.nih.gov/36717220/

2. Wang, Lina, Zhu, Lefan, Liang, Cong, Wong, Chi Chun, Yu, Jun. 2023. Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts antitumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis. In Journal of hepatology, 79, 1185-1200. doi:10.1016/j.jhep.2023.06.021. https://pubmed.ncbi.nlm.nih.gov/37459919/

3. Sun, Yu, Dong, Dan, Xia, Yuhong, Wang, Wei, Zhao, Chenghai. 2022. YTHDF1 promotes breast cancer cell growth, DNA damage repair and chemoresistance. In Cell death & disease, 13, 230. doi:10.1038/s41419-022-04672-5. https://pubmed.ncbi.nlm.nih.gov/35279688/

4. Rong, Haichuan, Wang, Danyang, Wang, Yiran, Dong, Chenshuang, Wang, Guiling. 2023. YTHDF1 in Tumor Cell Metabolism: An Updated Review. In Molecules (Basel, Switzerland), 29, . doi:10.3390/molecules29010140. https://pubmed.ncbi.nlm.nih.gov/38202722/