Platinum drug reprogramming of protein phosphorylation

Cisplatin is a DNA-targeting chemotherapeutic. We have utilized a forward chemical genetics strategy to map 7585 cisplatin-damaged genes (CDGs) with a fold-enrichment of >12 from A549 human lung cancer cells. The highly associated signalling pathways of the CDGs include sperm motility, molecular mechanism of cancer, and protein kinase A signalling. Among the CDGs, there are 1330 enzyme, 747 transcription regulators and 486 transporter genes. Importantly, cisplatin targets 306 protein kinase genes, accounting for 59% of putative protein kinase genes in the human genome, and 92 protein phosphatase genes which account for 67.6% of all protein phosphatases in the human genome. This suggests that cisplatin can reprogram protein phosphorylation genome-wide, evidenced by cisplatin-induced reduction in expression of 7 protein kinase genes in the sperm motility signalling pathway, and by CRISPR/dCas9-mediated imaging, which showed that cisplatination on the PTPRN2 gene recruits HMGB1, but repels Smad3, a transcription factor. Silencing NCCIT testicular cancer cell SPAG9 , which expresses JIP-4 in testicular haploid germ cells to activate MAPK signalling, resulted in similar apoptosis-inducing activity to cisplatin, implicating SPAG9 as a potential target for precise testicular cancer therapy.