Oncogenic zinc finger protein ZNF322A promotes lung cancer stemness through transcriptionally suppressing c-Myc expression [RNA-Seq]

ZNF322A, a C2H2 zinc finger transcription factor, is an oncoprotein in lung cancer. However, the transcription mechanisms of ZNF322A in lung cancer stemness remain elusive. By integrating our chromatin immunoprecipitation-sequencing and RNA-sequencing datasets, we identified and validated transcriptional targets of ZNF322A, which significantly enriched in developmental processes. Indeed, overexpression of ZNF322A promoted self-renewal ability and increased stemness-related gene expressions in vitro and in vivo. Importantly, ZNF322A bound directly to c-Myc promoter to transcriptionally suppress c-Myc expression, which in turn increased mitochondrial oxidative phosphorylation, promoted cell motility and thus maintained lung cancer stemness properties. Clinically, ZNF322AHigh/c-MycLow expression profile was revealed as an independent factor for poor outcome of lung cancer patients. Our study provides first evidence that ZNF322A-centered transcriptome promotes lung tumorigenesis and ZNF322A acts as a transcription suppressor of c-Myc to maintain lung cancer stemness by shifting metabolism phenotype to oxidative phosphorylation. Overall design: mRNA profiles of A549 lung cancer cells treated with control or si-ZNF322A oligo were generated by RNA-sequencing

ZNF322A作为一种C2H2型锌指转录因子（C2H2 zinc finger transcription factor），是肺癌中的癌蛋白。然而，ZNF322A在肺癌干性维持中的转录调控机制仍不明确。本研究整合了自有染色质免疫沉淀测序（chromatin immunoprecipitation-sequencing）与RNA测序（RNA-sequencing）数据集，鉴定并验证了ZNF322A的转录靶基因，这些靶基因显著富集于发育相关生物学过程。实验结果证实，ZNF322A过表达可在体内外增强细胞自我更新能力，并上调干性相关基因的表达水平。尤为关键的是，ZNF322A可直接结合至c-Myc启动子区域，从转录层面抑制c-Myc的表达，进而提升线粒体氧化磷酸化水平、促进细胞迁移，最终维持肺癌干性表型。临床数据分析显示，ZNF322A高表达/c-Myc低表达的表达谱可作为肺癌患者不良预后的独立危险因素。本研究首次揭示了以ZNF322A为核心的转录组可促进肺癌发生，并证实ZNF322A通过将细胞代谢表型转向氧化磷酸化，作为c-Myc的转录抑制因子维持肺癌干性。整体实验设计：采用RNA测序技术，对经阴性对照或si-ZNF322A寡核苷酸处理的A549肺癌细胞的mRNA表达谱进行检测。