| Summary: | 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 <i>CERK</i> expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. <i>CERK</i> 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 <i>CERK</i>: (i) expression of <i>CERK</i> is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce <i>CERK</i> mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific <i>Pten</i> deletion) results in elevated <i>Cerk</i> mRNA levels in prostate tissue. Mechanistically, we found that AR represses <i>CERK</i> 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 <i>CERK</i> in PCa.
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