m6A modification promotes EMT and metastasis of castration-resistant prostate cancer by upregulating NFIB
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Cancer research - (2024) vom: 27. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shu, Feng [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 27.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1158/0008-5472.CAN-23-1954 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370256697 |
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| 245 | 1 | 0 | |a m6A modification promotes EMT and metastasis of castration-resistant prostate cancer by upregulating NFIB |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Chen, Xiaohui |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Jiangli |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Wanwei |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shanshan |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Yili |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Rongna |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hongsheng |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Guanmin |e verfasserin |4 aut | |
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