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.

胰岛素受体酪氨酸激酶底物（insulin receptor tyrosine kinase substrate, IRTKS）的异常表达已被证实与多种肿瘤的发生发展密切相关，但其确切的调控机制，尤其是表观遗传事件，至今仍不明确。本研究发现，IRTKS表达上调可通过招募去泛素化酶OTUD4（deubiquitinase OTUD4），清除组蛋白甲基转移酶SETDB1（histone methyltransferase SETDB1）在K182与K1050位点的赖氨酸48位连接的多泛素化修饰，进而促进SETDB1的积累，最终特异性提升组蛋白H3赖氨酸9三甲基化（histone H3 lysine 9 trimethylation, H3K9me3）水平。充分激活的IRTKS-OTUD4-SETDB1-H3K9me3信号轴可降低染色质可及性，抑制上皮钙黏蛋白（E-cadherin）的转录，最终促进上皮间质转化（epithelial-mesenchymal transition, EMT）与肿瘤转移。临床数据分析显示，肿瘤标本中IRTKS的表达水平与SETDB1呈正相关，且二者的高表达与癌症患者的总生存期呈负相关。综上，本研究结果揭示，IRTKS可协同OTUD4，增强负责H3K9me3修饰的SETDB1的稳定性；该修饰与染色质可及性、上皮钙黏蛋白转录及EMT密切相关，这一发现为理解表观遗传调控驱动的肿瘤转移机制提供了深刻的认知。