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

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

  • Cancers (Basel). 2021 Aug 26;13(17):4307. doi: 10.3390/cancers13174307.
Laura Camacho 1 2 Amaia Zabala-Letona 1 3 Ana R Cortazar 1 3 Ianire Astobiza 1 Asier Dominguez-Herrera 2 Amaia Ercilla 1 3 Jana Crespo 1 Cristina Viera 1 Sonia Fernández-Ruiz 1 3 Ainara Martinez-Gonzalez 1 Veronica Torrano 1 2 3 Natalia Martín-Martín 1 3 Antonio Gomez-Muñoz 2 Arkaitz Carracedo 1 2 3 4
Affiliations

Affiliations

  • 1 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.
  • 2 Biochemistry and Molecular Biology Department, University of the Basque Country, 48040 Bilbao, Spain.
  • 3 Centro de Investigación Biomédica En Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
  • 4 IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain.
Abstract

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.

Keywords

bioinformatics; ceramide kinase; mouse models; prostate cancer; sphingolipid metabolism.

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