Identification of Androgen Receptor Metabolic Correlome Reveals the Repression of Ceramide Kinase by Androgens.

Laura Camacho,Ana R Cortazar,Asier Dominguez-Herrera,Amaia Zabala-Letona,Ianire Astobiza,Arkaitz Carracedo,Cristina Viera,Sonia Fernández-Ruiz,Natalia Martín-Martín,Amaia Ercilla,Ainara Martinez-Gonzalez,Antonio Gomez-Muñoz,Veronica Torrano,Jana Crespo

doi:10.3390/cancers13174307

Abstract

Simple SummaryProstate cancer cells require androgens to survive and grow. In turn, targeting androgen signaling has become a predominant therapeutic strategy in this disease. These hormones regulate a plethora of biological processes, which identification could aid the refinement of future anticancer treatments. Our aim was to uncover metabolic processes under the control of androgens, taking advantage of bioinformatics analyses using publicly accessible data in prostate cancer. We found that these hormones control the abundance of an enzyme, ceramide kinase (CERK). CERK produces ceramide-1-phosphate, a metabolite with prosurvival and migration properties. This finding suggests that antiandrogen therapies could be limited by the reactivation of this metabolic process. Prostate cancer (PCa) is one of the most prevalent cancers in men. Androgen receptor signaling plays a major role in this disease, and androgen deprivation therapy is a common therapeutic strategy in recurrent disease. Sphingolipid metabolism plays a central role in cell death, survival, and therapy resistance in cancer. Ceramide kinase (CERK) catalyzes the phosphorylation of ceramide to ceramide 1-phosphate, which regulates various cellular functions including cell growth and migration. Here we show that activated androgen receptor (AR) is a repressor of CERK expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. CERK was among the most prominent negatively correlated genes in our analysis. Interestingly, we demonstrated through various experimental approaches that activated AR reduces the mRNA expression of CERK: (i) expression of CERK is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce CERK mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific Pten deletion) results in elevated Cerk mRNA levels in prostate tissue. Mechanistically, we found that AR represses CERK through interaction with its regulatory elements and that the transcriptional repressor EZH2 contributes to this process. In summary, we identify a repressive mode of AR that influences the expression of CERK in PCa.

Highlights

Hormone signaling governs the molecular activity of an important fraction of cells in our body
To identify metabolic processes regulated by androgen receptors (AR) signaling in Prostate cancer (PCa), we undertook a bioinformatics approach (Figure 1A)
We showed that EZH2 was significantly associated with the AR-binding region in Ceramide kinase (CERK) AR site 1 (Figure 3D)

Summary

Introduction

Hormone signaling governs the molecular activity of an important fraction of cells in our body. Androgens activate androgen receptors (AR) to elicit a broad transcriptional program [4]. These steroids induce a conformational change in AR that promotes its dimerization, translocation to the nucleus, and association with Androgen Response Elements (ARE) in the DNA [4]. Similar to their normal counterparts, prostate cancer cells require androgen signaling to survive and proliferate [5,6,7]. It is essential to deconstruct the molecular events that account for ADT efficacy and drug resistance

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