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Published on: March 6, 2018
Phase Separation of NFIB Suppresses SLC3A2-Mediated Ferroptosis in Castration-Resistant Prostate Cancer
Qiunuo Li1, Danyang Chen2, Yongzhen Xia1
1Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.
Abstract:
Castration-resistant prostate cancer (CRPC) is frequently resistant to conventional therapies and lacks effective treatment options. Although CRPC cells exhibit sensitivity to ferroptosis inducers, the mechanisms regulating ferroptosis remain unclear. Here, we identify nuclear factor I/B (NFIB) as a critical suppressor of ferroptosis in CRPC. NFIB is upregulated in CRPC tissues and cell lines, positively correlating with SLC3A2, a critical subunit of System Xc-. NFIB knockout enhances erastin-induced ferroptosis, marked by elevated Fe2 +, MDA, and ROS levels. Mechanistically, NFIB directly activates SLC3A2 transcription and forms nuclear condensates through intrinsically disordered regions at both the N-terminus (1-69) and C-terminus (173-495), with the C-terminal IDR additionally supporting nuclear localization. Moreover, SIRT7-dependent deacetylation of NFIB regulates acetylation at K65 within the N-terminal IDR, thereby tuning condensate dynamics. K65 mutation reduces condensate liquidity and weakens NFIB-driven SLC3A2 transcriptional activation, resulting in enhanced ferroptosis. In vivo, combined NFIB suppression and ferroptosis induction significantly inhibit tumor growth and increase lipid peroxidation in CRPC xenografts. These findings uncover a critical role of NFIB phase separation and acetylation in ferroptosis regulation and suggest NFIB as a promising therapeutic target in CRPC.
Insights
Nuclear factor I/B (NFIB) suppresses ferroptosis in castration-resistant prostate cancer (CRPC). Inhibiting NFIB enhances ferroptosis, offering a new therapeutic strategy for CRPC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Castration-resistant prostate cancer (CRPC) presents significant therapeutic challenges due to resistance to conventional treatments.
- While CRPC cells are sensitive to ferroptosis, the underlying regulatory mechanisms are not fully understood.
Purpose of the Study:
- To identify key regulators of ferroptosis in CRPC.
- To elucidate the role of Nuclear Factor I/B (NFIB) in ferroptosis suppression within CRPC.
Main Methods:
- NFIB expression analysis in CRPC tissues and cell lines.
- CRISPR-Cas9 mediated NFIB knockout to assess ferroptosis induction.
- Investigation of NFIB's interaction with SLC3A2 and its role in transcriptional activation.
- Analysis of NFIB nuclear condensate formation and regulation by SIRT7-dependent deacetylation.
- In vivo studies using CRPC xenografts to evaluate therapeutic efficacy.
Main Results:
- NFIB is upregulated in CRPC and positively correlates with SLC3A2, a component of System Xc-.
- NFIB knockout potentiates erastin-induced ferroptosis, evidenced by increased Fe2+, MDA, and ROS.
- NFIB directly activates SLC3A2 transcription and forms regulatory nuclear condensates, influenced by SIRT7-mediated deacetylation at K65.
- Targeting NFIB in combination with ferroptosis inducers significantly reduces tumor growth and increases lipid peroxidation in vivo.
Conclusions:
- NFIB acts as a critical suppressor of ferroptosis in CRPC by regulating SLC3A2 expression and forming dynamic nuclear condensates.
- SIRT7-dependent deacetylation of NFIB is crucial for its condensate formation and ferroptosis-suppressive function.
- NFIB represents a promising therapeutic target for enhancing ferroptosis and treating CRPC.
