IRTKS，也被称为BAIAP2L1，在许多肿瘤中表达增强和遗传异常，特别是在肿瘤进展中观察到，然而，IRTKS增强肿瘤进展的分子和细胞机制尚不清楚。我们在这里展示，较高的IRTKS水平通过促进组蛋白甲基转移酶SETDB1的积累，特异性地增加了组蛋白H3赖氨酸9三甲基化（H3K9me3）。此外，我们揭示了IRTKS招募去泛素化酶OTUD4去除SETDB1的K182/K1050位点的Lys48链化多泛素化，从而通过泛素-蛋白酶体途径阻断SETDB1的降解。有趣的是，增强的IRTKS-OTUD4-SETDB1-H3K9me3轴导致染色质可及性的普遍降低，抑制了编码维持上皮细胞表型关键分子E-钙黏蛋白的CDH1的转录，从而导致上皮-间质转化（EMT）和恶性细胞转移。临床上，肿瘤标本中的IRTKS水平与SETDB1水平相关，但与生存时间呈负相关。我们的数据揭示了IRTKS增强肿瘤进展的新机制，其中IRTKS与OTUD4合作增强SETDB1介导的H3K9三甲基化，通过抑制E-钙黏蛋白表达促进肿瘤转移。该研究还提供了通过调节IRTKS或去泛素化酶OTUD4来降低已知治疗靶点SETDB1活性和稳定性的新潜在方法。版权所有 © 2023. 由Elsevier B.V.出版。

Elevated expression and genetic aberration of IRTKS, also named as BAIAP2L1, have been observed in many tumors, especially in tumor progression, however, the molecular and cellular mechanisms involved in the IRTKS-enhanced tumor progression are obscure. Here we show that higher IRTKS level specifically increases histone H3 lysine 9 trimethylation (H3K9me3) by promoting accumulation of the histone methyltransferase SETDB1. Furthermore, we reveal that IRTKS recruits the deubiquitinase OTUD4 to remove Lys48-linked polyubiquitination at K182/K1050 sites of SETDB1, thus blocking SETDB1 degradation via the ubiquitin-proteasome pathway. Interestingly, the enhanced IRTKS-OTUD4-SETDB1-H3K9me3 axis leads to a general decrease in chromatin accessibility, which inhibits transcription of CDH1 encoding E-cadherin, a key molecule essential for maintaining epithelial cell phenotype, and therefore results in epithelial-mesenchymal transition (EMT) and malignant cell metastasis. Clinically, the elevated IRTKS level in tumor specimens correlates with SETDB1 level, but negatively associated with survival time. Our data reveal a novel mechanism for the IRTKS-enhanced tumor progression, where IRTKS cooperates with OTUD4 to enhance the SETDB1-mediated H3K9 trimethylation that promotes tumor metastasis via suppressing E-cadherin expression. This study also provides a new potential approach to reduce the activity and stability of the known therapeutic target SETDB1 possibly through regulating IRTKS or deubiquitinase OTUD4.Copyright © 2023. Published by Elsevier B.V.