20(S)-Protopanaxatriol promotes the binding of P53 and DNA to regulate the antitumor network via multiomic analysis
Zhihua Wang, Wenbo Wu, Xiangchen Guan, Shuang Guo, Chaowen Li, Ruixue Niu, Jie Gao, Min Jiang, Li‐Ping Bai, Elaine Lai‐Han Leung, Yuanyuan Hou, Zhi‐Hong Jiang, Gang Bai
Abstract
Although the tumor suppressor P53 is known to regulate a broad network of signaling pathways, it is still unclear how certain drugs influence these P53 signaling networks. Here, we used a comprehensive single-cell multiomics view of the effects of ginsenosides on cancer cells. Transcriptome and proteome profiling revealed that the antitumor activity of ginsenosides is closely associated with P53 protein. A miRNA–proteome interaction network revealed that P53 controlled the transcription of at least 38 proteins, and proteome-metabolome profiling analysis revealed that P53 regulated proteins involved in nucleotide metabolism, amino acid metabolism and “Warburg effect”. The results of integrative multiomics analysis revealed P53 protein as a potential key target that influences the anti-tumor activity of ginsenosides. Furthermore, by applying affinity mass spectrometry (MS) screening and surface plasmon resonance fragment library screening, we confirmed that 20(S)-protopanaxatriol directly targeted adjacent regions of the P53 DNA-binding pocket and promoted the stability of P53–DNA interactions, which further induced a series of omics changes.