IRTKS enhances SETDB1-mediated H3K9 trimethylation that promotes tumor metastasis via recruiting deubiquitinase OTUD4

The abnormal expression of insulin receptor tyrosine kinase substrate (IRTKS) has been known to be involved in many tumors, however the defined mechanisms, especially epigenetic events, are still unclear. Here we show that the enhanced IRTKS specifically increases histone H3 lysine 9 trimethylation (H3K9me3) level via the histone methyltransferase SETDB1 accumulation, through recruiting the deubiquitinase OTUD4 to remove the Lys48-linked polyubiquitination at K182/K1050 sites of SETDB1. The adequate IRTKS-OTUD4-SETDB1-H3K9me3 axis leads to the decrease of chromatin accessibility and the inhibition of E-cadherin transcription, which ultimately promotes epithelial-mesenchymal transition (EMT) and tumor metastasis. Clinically, the elevated IRTKS in tumor specimens is in parallel with SETDB1 level, which is negatively associated with overall survival time of these cancer patients. In conclusion, our results uncover that IRTKS cooperates with the deubiquitinase OTUD4 to enhance the stability of SETDB1 responsible for H3K9me3 that is closely associated with chromatin accessibility, E-cadherin transcription, and the EMT, which provides a profound understanding of tumor metastasis by epigenetic progress.