Histone H3K27 demethylase UTX engages the DNA replication and repair pathways for tumor growth

Histone H3K27 demethylase UTX (aka KDM6A) is mutated in many human cancers,suggesting its tumor suppressive role during cancer development. However, most tumorsstill express wild-type UTX and its function is not always linked to tumor suppression. Here,we report a putative pro-oncogenic role of UTX in supporting tumor growth. We find thatUTX sustains tumor cell cycling and survival via regulating DNA replication-associatedtranscriptional programs in a demethylase-independent manner. UTX can also interact withPARP1 and facilitates its recruitment to DNA lesions. Interestingly, we identify differentessential UTX motifs involving in DNA replication and repair. UTX depletion impairs DNAreplication and repair pathways, leads to S and G2/M-phase arrest, and causes severetumor growth defect. Analysis of human cancer xenograft models further demonstrates thatUTX RNA-interference, but not GSK-J4 inhibition, shows potent anticancer effects. Our workhighlights UTX as a potential therapeutic target for tumors requiring its pro-oncogenicfunction.