GSE129696
Downregulation of polycomb repressive complex 2 mediates cisplatin acquired resistant in testicular germ cell tumors
A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies.  More than 80% of metastatic TGCT patients are cured with cisplatin-based chemotherapy. However, resistance can occur, which results in poor outcomes. The mechanisms of cisplatin hypersensitivity and resistance in these tumors and embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin acquired resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients.  Transcriptomics revealed highly significant alterations shared between resistant cells regardless of their parental origin. This included a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination and expression of BMI1.  Importantly repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients.  Our data indicates that repression of H3K27 methylation may be a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function could be a viable approach to overcome treatment failure. Overall design: gene expression of parental and cisplatin resistant cell lines in biological triplicate were analysed