The tumor-maintaining function of UTX/KDM6A in DNA replication and the PARP1-dependent repair pathway

Histone H3K27 demethylase UTX (aka KDM6A) is mutated in many human cancers, suggesting its tumor suppressive role during cancer development. However, most tumors still express wild-type UTX/KDM6A and its function is not always linked to tumor suppression. This suggests that UTX could be a pleiotropic factor in tumorigenesis; its deficiency promotes tumor initiation, while its presence is required for tumor maintenance. Here, we present evidence of UTX/KDM6A's role in sustaining tumor growth, revealing its function in tumor maintenance. We find that UTX/KDM6A sustains tumor cell cycling and survival via regulating DNA replication-associated transcriptional programs in a demethylase-independent manner. UTX/KDM6A can also interact with PARP1 and facilitate its recruitment to DNA lesions. Therefore, UTX/KDM6A depletion disrupts DNA replication and repair pathways, activating ATM–CHK2 and ATR–CHK1 signaling pathways and triggering S and G2/M checkpoints, leading to a pronounced defect in tumor growth. Analysis of human cancer xenograft models further demonstrates that knockdown of UTX/KDM6A by RNA-interference, rather than inhibition of its enzymatic activity via GSK-J4, shows potent anticancer effects. Dual inhibition of UTX/KDM6A and ATR further demonstrates synergistic anticancer activities. Our work highlights UTX/KDM6A as a potential therapeutic target for cancer treatment, especially when combined with ATR inhibition.