Camacho Laura, Zabala-Letona Amaia, Cortazar Ana R, Astobiza Ianire, Dominguez-Herrera Asier, Ercilla Amaia, Crespo Jana, Viera Cristina, Fernández-Ruiz Sonia, Martinez-Gonzalez Ainara, Torrano Veronica, Martín-Martín Natalia, Gomez-Muñoz Antonio, Carracedo Arkaitz
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.
Biochemistry and Molecular Biology Department, University of the Basque Country, 48040 Bilbao, Spain.
Cancers (Basel). 2021 Aug 26;13(17):4307. doi: 10.3390/cancers13174307.
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 expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. 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) expression of is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific deletion) results in elevated mRNA levels in prostate tissue. Mechanistically, we found that AR represses 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 in PCa.
前列腺癌（PCa）是男性中最常见的癌症之一。雄激素受体信号传导在这种疾病中起主要作用，雄激素剥夺疗法是复发性疾病的常见治疗策略。鞘脂代谢在癌症的细胞死亡、存活和治疗抗性中起核心作用。神经酰胺激酶（CERK）催化神经酰胺磷酸化为神经酰胺1-磷酸，后者调节包括细胞生长和迁移在内的各种细胞功能。在这里，我们表明活化的雄激素受体（AR）是一种表达抑制剂。我们采用生物信息学策略，利用PCa转录组数据集来确定与AR活性相关的代谢改变。在我们的分析中，是最显著的负相关基因之一。有趣的是，我们通过各种实验方法证明，活化的AR降低了的mRNA表达：（i）在AR活性低或为阴性的细胞系中，的表达占主导；（ii）AR激动剂和拮抗剂分别抑制和诱导mRNA表达；（iii）野生型小鼠或患有PCa（携带前列腺特异性缺失）的小鼠进行睾丸切除术后，前列腺组织中的mRNA水平升高。从机制上讲，我们发现AR通过与其调控元件相互作用来抑制，并且转录抑制因子EZH2参与了这一过程。总之，我们确定了AR的一种抑制模式，该模式影响PCa中基因的表达。
