m6A Modification Promotes EMT and Metastasis of Castration-Resistant Prostate Cancer by Upregulating NFIB

作者：Feng Shu, Hao Liu, Xiaohui Chen, Ye Liu, Jiangli Zhou, Lei Tang, Wanwei Cao, Shanshan Yang, Yili Long, Rongna Li, Hao Wang, Hongsheng Wang, Guanmin Jiang · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/0008-5472.can-23-1954 · 被引用次数：49 · 研究领域：RNA modifications and cancer、Signaling Pathways in Disease、Cancer-related gene regulation

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 tha...