The widespread use of androgen receptor (AR) signaling inhibitors has led to an increased incidence of AR-negative castration-resistant prostate cancer (CRPC), limiting effective treatment and patient survival. A more comprehensive understanding of the molecular mechanisms supporting AR-negative CRPC could reveal therapeutic vulnerabilities to improve treatment. This study showed that the transcription factor nuclear factor I/B (NFIB) was upregulated in AR-negative CRPC patient tumors and cell lines and was positively associated with an epithelial-to-mesenchymal transition (EMT) phenotype. Loss of NFIB inhibited EMT and reduced migration of CRPC cells. NFIB directly bound to gene promoters and regulated the transcription of EMT-related factors E-cadherin and vimentin, independently of other typical EMT-related transcriptional factors. In vivo data further supported the positive role of NFIB in the metastasis of AR-negative CRPC cells. Moreover, N6-methyladenosine (m6A) modification induced NFIB upregulation in AR-negative CRPC. Mechanistically, the m6A levels of mRNA, including NFIB and its E3 ubiquitin ligase TRIM8, were increased in AR-negative CRPC cells. Elevated m6A methylation of NFIB mRNA recruited YTHDF2 to increase mRNA stability and protein expression. Inversely, the m6A modification of TRIM8 mRNA, induced by ALKBH5 downregulation, decreased its translation and expression, which further promoted NFIB protein stability. Overall, this study reveals that upregulation of NFIB, mediated by m6A modification, triggers EMT and metastasis in AR-negative CRPC. Targeting the m6A/NFIB axis is a potential prevention and treatment strategy for AR-negative CRPC metastasis.

中文翻译：

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m6A修饰通过上调NFIB促进去势抵抗性前列腺癌的EMT和转移

雄激素受体（AR）信号抑制剂的广泛使用导致AR阴性去势抵抗性前列腺癌（CRPC）的发病率增加，限制了有效治疗和患者生存。更全面地了解支持 AR 阴性 CRPC 的分子机制可以揭示治疗的弱点，从而改善治疗。这项研究表明，转录因子核因子 I/B (NFIB) 在 AR 阴性 CRPC 患者肿瘤和细胞系中表达上调，并且与上皮间质转化 (EMT) 表型呈正相关。 NFIB 的缺失会抑制 EMT 并减少 CRPC 细胞的迁移。 NFIB直接与基因启动子结合并调节EMT相关因子E-钙粘蛋白和波形蛋白的转录，独立于其他典型的EMT相关转录因子。体内数据进一步支持 NFIB 在 AR 阴性 CRPC 细胞转移中的积极作用。此外，N6-甲基腺苷 (m6A) 修饰诱导 AR 阴性 CRPC 中 NFIB 上调。从机制上讲，AR 阴性 CRPC 细胞中 mRNA（包括 NFIB 及其 E3 泛素连接酶 TRIM8）的 m6A 水平升高。 NFIB mRNA 的 m6A 甲基化升高会招募 YTHDF2 来增加 mRNA 稳定性和蛋白质表达。相反，ALKBH5 下调诱导的 TRIM8 mRNA 的 m6A 修饰降低了其翻译和表达，从而进一步促进了 NFIB 蛋白的稳定性。总体而言，这项研究表明，m6A 修饰介导的 NFIB 上调可触发 AR 阴性 CRPC 中的 EMT 和转移。靶向 m6A/NFIB 轴是 AR 阴性 CRPC 转移的潜在预防和治疗策略。