ATR inhibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D
Kazumasa Komura, … , Christopher J. Sweeney, Philip W. Kantoff
Kazumasa Komura, … , Christopher J. Sweeney, Philip W. Kantoff
Published June 4, 2018
Citation Information: J Clin Invest. 2018;128(7):2979-2995. https://doi.org/10.1172/JCI96769.
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Research Article Genetics Oncology Article has an altmetric score of 13

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.

Authors

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

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Figure 4

Pathways affected by the modification of KDM5D expression levels.

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Pathways affected by the modification of KDM5D expression levels. (A) Ve...
(A) Venn diagram from RNA-seq analysis comparing differentially expressing genes with FDR < 0.01 in LNCaP sh-control vs. sh-KDM5D#1, sh-KDM5D#3, and 104R2 pLenti-control versus pLenti-KDM5D. (B) Heatmap of RNA-seq analysis comparing the differentially expressed genes of 143 negatively collated genes and 28 positively correlated genes with KDM5D expression level. Top 20 GO terms of FDR < 0.05 in genes of negative correlation are shown. sh-C, control; sh-K, KDM5D. (C) Top 2 positively and negatively enriched pathways by knockdown (in LNCaP sh-control vs. sh-KDM5D#1) and overexpression (in LNCaP-104R2 control vs. overexpression) of KDM5D, respectively. Pathways were sorted by normalized enrichment score (NES) in GSEA. (D) Peak map of KDM5D and H3K4 methylation marks near the transcription start site of MCM10 and NUF2 in LNCaP sh-control and sh-KDM5D#1 cells. ChIP-qPCR was performed using primers indicated in peak map, and results of 3 independent experiments are shown as mean + SD. *P < 0.05, unpaired t test.