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In vivo genome-wide CRISPR screening identifies ZNF24 as a negative NF-κB modulator in lung cancer
Lu Liu1, Yuxi Lei1, Wensheng Chen1
1MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
Abstract:
Systemic identification of tumor suppressor genes (TSGs) and elucidation of their signaling provide a new angle for understanding of tumorigenesis, which is important for developing successful treatment for lung cancer patients. In our current work, we conducted an in vivo screen for lung cancer TSGs through CRISPR/Cas9 mediated knockout of genes at genome-wide scale. We found that ZNF24 was a potent and clinically relevant TSG of lung cancer. Ectopic expression of ZNF24 arrested lung cancer cells in S phase. Mechanistically, ZNF24 bound to promoter region of P65 to negatively regulate its transcription and thereby the signaling activity of NF-κB pathway. This signaling cascade is clinically relevant. Importantly, we found that combinational inhibition of KRAS, NF-κB, and PD-1 effectively shrank autochthonous KrasG12D/ZNF24-/- lung cancers in transgenic mouse model. Our current work thus revealed an important role played by loss of function of ZNF24 in lung tumorigenesis and shed new light in precision medicine for a portion of lung cancer patients.
Insights
Zinc finger protein 24 (ZNF24) acts as a tumor suppressor gene in lung cancer. Loss of ZNF24 promotes tumor growth by activating NF-κB signaling, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumor suppressor genes (TSGs) are crucial for understanding cancer development.
- Identifying novel TSGs and their roles in tumorigenesis is vital for effective lung cancer treatment.
Purpose of the Study:
- To identify novel lung cancer TSGs using a genome-wide CRISPR/Cas9 screen.
- To elucidate the molecular mechanisms by which ZNF24 suppresses lung cancer.
- To explore therapeutic strategies targeting ZNF24 loss-of-function in lung cancer.
Main Methods:
- Genome-wide in vivo CRISPR/Cas9 knockout screen for lung cancer TSGs.
- Analysis of ZNF24's effect on lung cancer cell cycle progression.
- Investigation of ZNF24's interaction with the NF-κB pathway components.
- Evaluation of combination therapy in a KrasG12D/ZNF24-/- transgenic mouse model.
Main Results:
- ZNF24 was identified as a potent and clinically relevant lung cancer TSG.
- Ectopic ZNF24 expression induced S-phase arrest in lung cancer cells.
- ZNF24 directly suppressed P65 transcription, inhibiting the NF-κB pathway.
- Combination therapy targeting KRAS, NF-κB, and PD-1 significantly reduced tumor burden in a mouse model.
Conclusions:
- Loss of ZNF24 function contributes to lung tumorigenesis through NF-κB pathway activation.
- ZNF24 represents a potential therapeutic target for precision medicine in lung cancer.
- Combined inhibition strategies show promise for treating lung cancers with ZNF24 deficiency.
