ATR inhibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D

Abstract

Epigenetic modifications control cancer development and clonal evolution in various cancer types. Here, we show that loss of the male-specific histone demethylase lysine-specific demethylase 5D (KDM5D) encoded on the Y chromosome epigenetically modifies histone methylation marks and alters gene expression, resulting in aggressive prostate cancer. Fluorescent in situ hybridization demonstrated that segmental or total deletion of the Y chromosome in prostate cancer cells is one of the causes of decreased KDM5D mRNA expression. The result of ChIP-sequencing analysis revealed that KDM5D preferably binds to promoter regions with coenrichment of the motifs of crucial transcription factors that regulate the cell cycle. Loss of KDM5D expression with dysregulated H3K4me3 transcriptional marks was associated with acceleration of the cell cycle and mitotic entry, leading to increased DNA-replication stress. Analysis of multiple clinical data sets reproducibly showed that loss of expression of KDM5D confers a poorer prognosis. Notably, we also found stress-induced DNA damage on the serine/threonine protein kinase ATR with loss of KDM5D. In KDM5D-deficient cells, blocking ATR activity with an ATR inhibitor enhanced DNA damage, which led to subsequent apoptosis. These data start to elucidate the biological characteristics resulting from loss of KDM5D and also provide clues for a potential novel therapeutic approach for this subset of aggressive prostate cancer.

Disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human Y chromosome as a self-domestication syndrome

“…The human KDM5D gene encoding lysine demethylase 5D contains three SNPs (e.g., rs113917966) that reduce the expression of this gene (Table S 4 ). According to a PubMed keyword search, KDM5D underexpression occurs in patients with prostate cancer often enough [ 78 ] to propose these three SNPs as candidate SNP markers of a decrease in male reproductive potential (Table S 4 ).…”

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

“…KDM5C promotes cell motility and invasion in breast and hepatocellular cancer 112,113 , and is overexpressed in prostate cancer 114 , but behaves as a tumor suppressor in renal cancer 115 . Studies of KDM5D (JARID1D/SMCY), a KDM5C paralog located on the Y chromosome, have thus far demonstrated loss, and functionally a metastasis-suppressive role, in prostate cancer [116][117][118] .…”

Network Medicine Approach for Analysis of Alzheimer’s Disease Gene Expression Data

“…The third member of this group of Y-linked genes is USP9Y, which is a protease which cleaves ubiquitin from ubiquitinylated proteins and ubiquitin-fused precursors [29]. The last of the Y-linked genes in this set is KD5MD, which is a male lysine-specific histone demethylase that regulates transcription factors that modulate the cell cycle [30]. As one might expect of these four genes, they are all directly connected on the positive-correlation networks of every disease condition, and all three are over-expressed in both MCI and AD individuals.…”