Retinoic acid receptors and LSD1 as novel targets for prostate cancer
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Castration resistant prostate cancer (CRPC) is the most aggressive and lethal form of prostate cancer (PCa) and novel therapies are required for its treatment. Epigenetic and genetic alterations are very common in CRPC cells and contribute to the cancer phenotype by promoting aberrant gene expression. Nuclear receptors, modulated by co-repressor and co-activator complexes, orchestrate the cells transcriptional landscape to activate and repress downstream pathways, ultimately affecting cell growth and survival. Retinoic acid receptors (RAR) are retinoic acid (RA) regulated nuclear receptors that play a key role on cell differentiation and can induce apoptosis in tumor cells. On the other hand, LSD1, a co-regulatory protein, is overexpressed in cancer tissues and alters the activity of the androgen receptor, driving carcinogenesis. In RA resistant acute myeloid leukemia cells, inhibition of LSD1 reactivates RA induced differentiation and combinatorial therapy of a LSD1 antagonist and all-trans RA promotes apoptosis. We suggest a combinatorial therapeutic approach by inhibiting LSD1 and activating RAR. To determine whether gene expression patterns involving LSD1 and RAR are altered in the tumor tissue, RNA-Sequencing (RNA-Seq) data from 52 matched normal and tumor samples available from the cancer genome atlas (TCGA) database were analyzed using R programming language (limma package). Approximately 28% of the retinoid metabolism genes, 11% of RAR and 10% of LSD1 signature genes were differentially expressed with a log2 FC > ±1 and FDR < 0.05. All three subtypes of RARs and their heterodimeric partners retinoid X receptors (RXRs), also a great majority of the retinol metabolism genes were significantly downregulated in the tumor tissue. Additionally majority of the genes that are involved in RA metabolism and signaling showed a significant negative correlation to LSD1 expression. Subsequently, cell proliferation assays were performed on stably transfected shLSD1 LNCaP-C4-2 (C4-2) cells, treated with RA or vehicle control, to evaluate the phenotypical consequences of targeting RAR and LSD1. C4-2 cells treated with RA in combination with LSD1 knock-down showed significantly higher inhibition of proliferation when compared to control or RA treated control cells. Additionally, in order to analyze the effect of the combinatorial therapy with LSD1 inhibition and ATRA treatment on the C4-2 cell transcriptome, RNA-Sequencing experiment was conducted on LSD1-targeted shRNA transfected C4-2 cells. LSD1 inhibition enhanced the transcriptional response to ATRA and modulated apoptotic pathways. These results suggest the relevance of a combinatorial therapeutic approach targeting LSD1 and RAR in CRPCa cells.