YTHDF3-induced degradation of P4HA2 mRNA inhibits glycolysis in papillary thyroid cancer through Hippo signaling pathway.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.