Department of Oral and Maxillofacial Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Neoplasma. 2022 Jan;69(1):71-79. doi: 10.4149/neo_2021_210716N967. Epub 2021 Nov 16.
N6-methyladenosine (m6A) is the most common internal reversible modification of mRNA, which occurs on the N6 nitrogen of adenosine. Fat mass and obesity-associated (FTO) is a demethylase that erases m6A modification and has recently been linked to cancer. Herein, we explored the role of FTO in oral squamous cell carcinoma (OSCC). High FTO mRNA and protein levels were observed in OSCC cell lines and tissues as compared to normal controls. OSCC patients with high FTO displayed larger tumor size, higher TNM stage, poorer differentiation, and shorter survival time than those with low FTO. Stable knockdown of FTO inhibited OSCC cell viability, colony formation, and tumor growth. Further, FTO depletion increased YAP1 m6A modification at mRNA 3'-untranslated region, accelerating the degradation of YAP1 mRNA, a well-documented oncogene promoting OSCC progression. Importantly, nucleocytoplasmic shuttling of FTO is critical for YAP1 mRNA demethylation and decay following YTHDF2 reading and recognition. Our results highlight the role of FTO in regulating YAP1 mRNA stability, and targeting of FTO/YAP1 axis may be a promising intervention for OSCC patients.
N6-甲基腺苷（m6A）是 mRNA 内部最常见的可逆修饰，发生在腺苷的 N6 氮上。脂肪量和肥胖相关（FTO）是一种去甲基酶，可消除 m6A 修饰，最近与癌症有关。在此，我们探讨了 FTO 在口腔鳞状细胞癌（OSCC）中的作用。与正常对照组相比，OSCC 细胞系和组织中观察到 FTO mRNA 和蛋白水平较高。与 FTO 低表达的 OSCC 患者相比，FTO 高表达的患者肿瘤体积更大、TNM 分期更高、分化程度更低、生存时间更短。FTO 的稳定敲低抑制了 OSCC 细胞的活力、集落形成和肿瘤生长。此外，FTO 耗竭增加了 YAP1 mRNA 3′-非翻译区的 YTHDF2 阅读和识别后 YAP1 mRNA 的 m6A 修饰，加速了 YAP1 mRNA 的降解，众所周知，YAP1 mRNA 促进 OSCC 进展的癌基因。重要的是，FTO 的核质穿梭对于 YAP1 mRNA 去甲基化和衰变是至关重要的，这是在 YTHDF2 阅读和识别之后发生的。我们的研究结果强调了 FTO 在调节 YAP1 mRNA 稳定性中的作用，靶向 FTO/YAP1 轴可能是 OSCC 患者的一种有前途的干预措施。
