Dpep is a cell-penetrating peptide targeting transcription factors ATF5, CEBPB, and CEBPD, and that selectively promotes the apoptotic death of multiple tumor cell types in vitro and in vivo. As such, it is a potential therapeutic. To better understand its mechanism of action, we used PLATE-seq to compare the transcriptomes of six cancer cell lines of diverse origins before and after Dpep exposure. This revealed a context-dependent pattern of regulated genes that was unique to each line, but that exhibited a number of elements that were shared with other lines. This included the upregulation of pro-apoptotic genes and tumor suppressors as well as the enrichment of genes associated with responses to hypoxia and interferons. Downregulated transcripts included oncogenes and dependency genes, as well as enriched genes associated with different phases of the cell cycle and with DNA repair. In each case, such changes have the potential to lie upstream of apoptotic cell death. We also detected the regulation of unique as well as shared sets of transcription factors in each line, suggesting that Dpep may initiate a cascade of transcriptional responses that culminate in cancer cell death. Such death thus appears to reflect context-dependent, yet shared, disruption of multiple cellular pathways as well as of individual survival-relevant genes.
Dpep是一种靶向转录因子ATF5、CEBPB和CEBPPD的细胞穿透肽，在体外和体内能选择性促进多种肿瘤细胞类型的凋亡性死亡，因此具有潜在治疗价值。为深入理解其作用机制，我们采用PLATE-seq技术比较了六种不同来源的癌细胞系在Dpep处理前后的转录组变化。结果显示，各细胞系均呈现独特的背景依赖性基因调控模式，但同时也存在多系共有的调控特征：包括促凋亡基因和抑癌基因的上调，以及对缺氧和干扰素反应相关基因的富集。下调转录本则涉及癌基因、依赖性基因，以及与细胞周期各阶段和DNA修复相关的富集基因。这些变化均可能位于细胞凋亡死亡通路的上游。此外，我们在各细胞系中检测到独特及共有的转录因子调控集合，表明Dpep可能通过启动级联转录反应最终导致癌细胞死亡。由此可见，这种细胞死亡现象反映了多细胞通路及个体生存相关基因在背景依赖性调控下，通过共享机制被协同破坏的过程。
肿瘤(癌症)患者之家