DNA replication stress by the loss of male specific histone demethylase ‘KDM5D’ in aggressive prostate cancer
We previously demonstrated that loss of male specific histone demethylase &[prime]KDM5D&[prime] is associated with docetaxel resistance (Komura et al, 2016, PNAS). Decreased KDM5D expression seemed to be attributed to the deletion of copy number loss at Yq11 in prostate cancer.
RNAseq and ChIPseq were performed to elucidate the biological function of KDM5D using hormone sensitive LNCaP cells (KDM5D positive) and corresponding LNCaP-104R2 CRPC cells (KDM5D negative by copy number loss of Y chromosome). Clinical impact of the genes regulated by KDM5D were further examined in TCGA and Health Professionals Follow-Up Study (PHS/HPFS) cohorts.
Gene Set Enrichment Analysis (GSEA) from the data of RNAseq in LNCaP (control vs sh-KDM5D#1 and #3) and LNCaP-104R2 (control vs KDM5D overexpression) revealed 64 positively enriched and 101 negatively enriched pathways with a false discovery rate (FDR) <0.25 when KDM5D was knocked down in LNCaP and was overexpressed in LNCaP-104R2 cells, respectively. Strikingly, there was substantial overlap between the pathways upregulated with knockdown of KDM5D in LNCaP and those downregulated with overexpression of KDM5D in LNCaP-104R2, including DNA replication and mitotic related pathways (the top two gene sets) (Fig. 1). ChIP-seq analysis exhibited that Increased H3K4me3 signals, which were found to be active transcriptional marks, were detected in those pathways, suggesting DNA replication stress by loss of KDM5D. We finally identified 69 genes negatively correlated with KDM5D expression level from our in vitro analysis and clinically available datasets. Upregulation of those 69 genes seemed to contribute to the worse outcome in TCGA and PHS/HPFS cohorts (Figure 2). We also found that DNA replication stress by loss of KDM5D might cause chromosomal instability, which renders aggressive phenotype to prostate cancer cells.</p>
Loss of KDM5D causes aberrant DNA replication and mitotic activity leading to DNA replication stress, and those cells have a more aggressive phenotype with harboring chromosomal instability.
Funding: This work was partially supported by Department of Defense (DOD) (grant W81XWH-16-1-0639).