Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China.
Cancer Res. 2024 Jun 14;84(12):1947-1962. doi: 10.1158/0008-5472.CAN-23-1954.
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 patient with AR-negative CRPC 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 (CDH1) and vimentin (VIM), independent 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.
NFIB upregulation mediated by increased m6A levels in AR-negative castration-resistant prostate cancer regulates transcription of EMT-related factors to promote metastasis, providing a potential therapeutic target to improve prostate cancer treatment.
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，限制了有效的治疗和患者生存。更全面地了解支持 AR 阴性 CRPC 的分子机制可以揭示治疗弱点，以改善治疗效果。本研究表明，转录因子核因子 I/B（NFIB）在 AR 阴性 CRPC 肿瘤和细胞系中上调，并与上皮-间质转化（EMT）表型呈正相关。NFIB 的缺失抑制 EMT 并减少 CRPC 细胞的迁移。NFIB 直接与基因启动子结合，独立于其他典型的 EMT 相关转录因子，调节 EMT 相关因子 E-钙粘蛋白（CDH1）和波形蛋白（VIM）的转录。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 的上调。在机制上，AR 阴性 CRPC 细胞中包括 NFIB 及其 E3 泛素连接酶 TRIM8 的 mRNA 的 m6A 水平增加。NFIB mRNA 的 m6A 甲基化募集 YTHDF2 以增加 mRNA 稳定性和蛋白表达。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 NFIB 蛋白稳定性。总的来说，这项研究揭示了由 m6A 修饰介导的 NFIB 上调触发了 AR 阴性 CRPC 中的 EMT 和转移。靶向 m6A/NFIB 轴可能是预防和治疗 AR 阴性 CRPC 转移的潜在策略。
AR 阴性去势抵抗性前列腺癌中 m6A 水平增加介导的 NFIB 上调调节 EMT 相关因子的转录，促进转移，为改善前列腺癌治疗提供了一个潜在的治疗靶点。
