Login to Access Video or Poster Abstract: MP28-14
Sources of Funding: This work was supported by the Louis B. Mayer Foundation.

Introduction

We previously showed that decreased expression of the Lysine-Specific Demethylase &[prime]KDM5D&[prime] encoded on the Y chromosome was associated with docetaxel resistance (Komura et al, 2016, PNAS). We hypothesize that loss of KDM5D may significantly affect the epigenetic landscape in prostate cancer cells and facilitate the development of CRPC.

Methods

To elucidate biological function of KDM5D, we performed RNAseq analysis in hormone sensitive LNCaP cells (KDM5D positive) and corresponding LNCaP-104R2 CRPC cells (KDM5D negative). Individual genes which were found as potential targets of KDM5D were further explored in a publically available clinical database.

Results

We found 143 overlapping genes, which are upregulated by knockdown of KDM5D in LNCaP and down regulated by overexpression of KDM5D in 104R2 and 28 genes, which were down regulated by KDM5D knockdown in LNCaP and up-regulated by KDM5D overexpression in 104R2. Gene ontology (GO) analyses with FDR<0.05 from the 143 genes identified mitotic and cell cycle related genes as most commonly upregulated by loss of KDM5D (Figure 1). To validate the results, we explored the Taylor&[prime]s prostate cancer cohort with cBioportal. Of 8643 genes negatively correlated with KDM5D expression level (Pearson Correlation Coefficient < -0.3), 69 genes were identified in both our data and the Taylor&[prime]s cohort. Upregulation of these genes in CRPC was further confirmed in 2 publicly available datasets (PAD).2 (Figure 2). Finally in a PAD from a Mayo Clinic&[prime]s cohort (Illumina DASL Cancer Panel microarray) which included 8 genes out of the 69 genes, noted shorter cancer-specific mortality in pts with higher expression of those genes was demonstrated in all 8 genes.

Conclusions

Loss of KDM5D is associated with upregulation of mitotic and cell-cycle related genes which may lead to development of CRPC and serve as prognostic factor for its development.

Funding

This work was supported by the Louis B. Mayer Foundation.