Liu Lu, Lei Yuxi, Chen Wensheng, Zhou Qian, Zheng Zongyao, Zeng Guandi, Liu Wanting, Feng Pengju, Zhang Zhiyi, Yu Lei, Chen Liang
MOE 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.
Department of Chemistry, Jinan University, Guangzhou, 510632, China.
Cell Biosci. 2022 Dec 1;12(1):193. doi: 10.1186/s13578-022-00933-0.
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 Kras/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.
肿瘤抑制基因（TSGs）的系统鉴定及其信号传导的阐明为理解肿瘤发生提供了一个新视角，这对于开发成功的肺癌患者治疗方法至关重要。在我们当前的工作中，我们通过CRISPR/Cas9介导的全基因组范围基因敲除对肺癌TSGs进行了体内筛选。我们发现ZNF24是一种有效的且与临床相关的肺癌肿瘤抑制基因。ZNF24的异位表达使肺癌细胞停滞在S期。从机制上讲，ZNF24与P65的启动子区域结合以负向调节其转录，从而调节NF-κB途径的信号传导活性。这种信号级联与临床相关。重要的是，我们发现在转基因小鼠模型中，联合抑制KRAS、NF-κB和PD-1可有效缩小原发性Kras/ZNF24肺癌。我们当前的工作因此揭示了ZNF24功能丧失在肺癌发生中所起的重要作用，并为一部分肺癌患者的精准医学提供了新的思路。
