Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Science, Guizhou Medical University, Guiyang, Guizhou, China.
Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
J Pineal Res. 2024 Aug;76(5):e13003. doi: 10.1111/jpi.13003.
RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of SPOP and NXK3.1 but stabilized RNA expressions of TWIST1 and SNAI2 dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading SPOP in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity.
RNA N6-甲基腺苷（m6A）读码器介导癌症进展。然而，m6A 读码器在前列腺癌肿瘤发生中的功能作用和潜在机制仍有待阐明。在这项研究中，我们证明 YTHDF3 的表达在去势抵抗性前列腺癌（CRPC）中上调，并且与高级别、骨转移和不良预后呈正相关。YTHDF3 的表达促进了 CRPC 细胞的增殖、上皮间质转化（EMT）和肿瘤进展。在机制上，YTHDF3 通过促进 SPOP 和 NXK3.1 的 RNA 降解，但依赖于 m6A 稳定 TWIST1 和 SNAI2 的 RNA 表达，从而促进细胞增殖和 EMT。此外，YTHDF3 通过依赖于 m6A 的方式降解 SPOP 来增强 AKT 活性。重要的是，我们发现褪黑素可以与 m6A 竞争，占据 YTHDF3 的 m6A 结合笼，从而抑制 YTHFD3 及其靶基因的表达以及 CRPC 肿瘤的生长。我们的研究结果揭示了 YTHDF3 在 CRPC 进展中的重要作用，并强调了褪黑素在抗 CRPC 活性中的作用。
