Ding Ying, Liu Mengyuan, Wang Wenlong, Li Xinying
Department of Breast Thyroid Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; Postdoctoral Station of Medical Aspects of Specific Environments, the Third Xiangya Hospital, Central South University, Changsha, China; Thyroid Surgery Department, Xiangya Hospital, Central South University, Changsha 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China; Eye Center of Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
Int J Biol Macromol. 2025 Feb;291:139150. doi: 10.1016/j.ijbiomac.2024.139150. Epub 2024 Dec 24.
Prolyl-4-hydroxylase-A2 (P4HA2) is a pivotal enzyme involved in the regulation of tumorigenesis and progression. However, the precise biological roles and potential functions of P4HA2 in papillary thyroid cancer (PTC) remain poorly elucidated.
Gain-of-function and loss-of-function approaches were employed to investigate the underlying biological effects of P4HA2 on PTC cell proliferation and metastasis both in vitro and in vivo. Furthermore, RIP assay, MeRIP assay, polysome fractionation, dual luciferase reporter assay, LC-MS/MS, and rescue experiments were conducted to explore the intricate relationships between YTHDF3, P4HA2 and Hippo signaling pathway.
P4HA2 exhibited significant up-regulation in PTC and was associated with unfavorable clinical characteristics and prognosis. In vitro and in vivo experiments demonstrated that P4HA2 promoted PTC cell proliferation and metastasis, while also contributing to tumorigenesis through the activation of glycolysis. Mechanistically, P4HA2 facilitated hydroxylation-mediated ubiquitination and degradation of SAV1, leading to enhanced expression of YAP1 in the Hippo signaling pathway. Additionally, YTHDF3 binding to P4HA2 mRNA in an N6-methyladenosine (m6A)-dependent manner decreased its stability, thereby inhibiting glycolysis in PTC.
The YTHDF3-regulated P4HA2 acts as an oncogenic factor, regulating glycolysis in PTC through the Hippo signaling pathway. This suggests that P4HA2 holds potential as a promising diagnostic marker and therapeutic target for patients with PTC.
脯氨酰-4-羟化酶-A2（P4HA2）是一种参与肿瘤发生和进展调控的关键酶。然而，P4HA2在甲状腺乳头状癌（PTC）中的确切生物学作用和潜在功能仍不清楚。
采用功能获得和功能丧失方法，在体外和体内研究P4HA2对PTC细胞增殖和转移的潜在生物学效应。此外，进行了RNA免疫沉淀分析（RIP分析）、甲基化RNA免疫沉淀分析（MeRIP分析）、多核糖体分级分离、双荧光素酶报告基因分析、液相色谱-串联质谱（LC-MS/MS）和挽救实验，以探讨YTHDF3、P4HA2和Hippo信号通路之间的复杂关系。
P4HA2在PTC中显著上调，与不良临床特征和预后相关。体外和体内实验表明，P4HA2促进PTC细胞增殖和转移，同时通过激活糖酵解促进肿瘤发生。机制上，P4HA2促进SAV1的羟基化介导的泛素化和降解，导致Hippo信号通路中YAP1表达增强。此外，YTHDF3以N6-甲基腺苷（m6A）依赖的方式与P4HA2 mRNA结合，降低其稳定性，从而抑制PTC中的糖酵解。
YTHDF3调节的P4HA2作为一种致癌因子，通过Hippo信号通路调节PTC中的糖酵解。这表明P4HA2有望成为PTC患者的诊断标志物和治疗靶点。
