Abstract：
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.
摘要：
RNAN6-甲基腺苷(m6A)读取器介导癌症进展。然而,m6A阅读器在前列腺癌致瘤性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表达在去势抵抗性前列腺癌（CRPC）中升高，并且与高级别呈正相关，骨转移和低生存率。YTHDF3表达促进CRPC细胞增殖，上皮间质转化（EMT）和肿瘤进展。机械上,YTHDF3促进SPOP和NXK3.1的RNA降解，但稳定了依赖于m6A的TWIST1和SNAI2的RNA表达，以促进细胞增殖和EMT。此外,YTHDF3表达以m6A依赖性方式通过降解SPOP增强AKT活性。重要的是,我们发现褪黑激素可以与m6A竞争占据YTHDF3的m6A结合笼，导致抑制YTHFD3及其靶表达以及CRPC肿瘤生长。我们的发现揭示了YTHDF3在CRPC进展中的重要作用，并强调了褪黑激素在抗CRPC活性中的作用。
