Journal Article

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

Shimamura, Teppei, Gerke, Travis A., Azuma, Haruhito, Kantoff, Philip W., Armenia, Joshua, Komura, Kazumasa, Du, Shin-Yi, Ibuki, Naokazu, Chadalavada, Kalyani, Jeong, Seong Ho, Meyer, Clifford A., Mucci, Lorelei A., Chakraborty, Goutam, Mazzu, Ying Z., Hinohara, Kunihiko, Inamoto, Teruo, Sweeney, Christopher J., Yoshikawa, Yuki, Taniguchi, Kohei, Nanjangud, Gouri J., Lee, Gwo-Shu Mary

2018

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Androgens / Antiretroviral agents / Apoptosis / Bioinformatics / Biomedical research / Care and treatment / Cell cycle / Cell growth / Chromosome deletion / Chromosomes / Clonal deletion / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA damage / DNA methylation / DNA sequencing / Dosage and administration / Epigenetics / Fluorescence in situ hybridization / Gene expression / Genomes / Genomics / Hypotheses / Kinases / Lysine / Medical prognosis / Metastasis / Prostate cancer / Protein kinase / Protein-serine/threonine kinase / Proteins / Risk factors / Transcription factors / Tumors / Y chromosomes