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)
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).