Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Oncogene. 2021 Jan;40(3):592-602. doi: 10.1038/s41388-020-01553-z. Epub 2020 Nov 16.
A subset of human prostate cancer exhibits increased de novo synthesis of fatty acids, but the molecular driver(s) of this metabolic abnormality remains obscure. This study demonstrates a novel metabolic function of c-Myc (Myc) in regulation of fatty acid synthesis. The role of Myc in regulation of fatty acid synthesis was investigated by: (a) interrogation of the prostate cancer The Cancer Genome Atlas (TCGA) dataset, (b) chromatin immunoprecipitation, and (c) determination of the expression of fatty acid synthesis enzymes and targeted metabolomics using a mouse model and human specimens. The expression of MYC was positively associated with that of key fatty acid synthesis genes including ACLY, ACC1, and FASN in prostate cancer TCGA dataset. Chromatin immunoprecipitation revealed Myc occupancy at the promoters of ACLY, ACC1, and FASN. Prostate-specific overexpression of Myc in Hi-Myc transgenic mice resulted in overexpression of ACLY, ACC1, and FASN proteins in neoplastic lesions and increased circulating levels of total free fatty acids. Targeted metabolomics confirmed increased circulating levels of individual fatty acids in the plasma of Hi-Myc mice and human subjects when compared to corresponding controls. Immunohistochemistry also revealed a positive and statistically significant association in expression of Myc with that of ACC1 in human prostate adenocarcinoma specimens. We propose that Myc-regulated fatty acid synthesis is a valid target for therapy and/or prevention of prostate cancer.
一组人类前列腺癌表现出脂肪酸从头合成增加，但这种代谢异常的分子驱动因素尚不清楚。本研究展示了 c-Myc（Myc）在调节脂肪酸合成中的一种新的代谢功能。通过以下方法研究了 Myc 在调节脂肪酸合成中的作用：（a）对前列腺癌癌症基因组图谱（TCGA）数据集进行分析，（b）进行染色质免疫沉淀，（c）使用小鼠模型和人类标本确定脂肪酸合成酶的表达和靶向代谢组学。在前列腺癌 TCGA 数据集中，MYC 的表达与关键脂肪酸合成基因（包括 ACLY、ACC1 和 FASN）的表达呈正相关。染色质免疫沉淀显示 Myc 占据 ACLY、ACC1 和 FASN 启动子。在 Hi-Myc 转基因小鼠中特异性过表达 Myc 会导致肿瘤病变中 ACLY、ACC1 和 FASN 蛋白表达过度，并增加循环中总游离脂肪酸的水平。靶向代谢组学证实，与相应对照相比，Hi-Myc 小鼠和人类受试者的血浆中个体脂肪酸的循环水平升高。免疫组织化学还显示 Myc 与人类前列腺腺癌标本中 ACC1 的表达呈正相关且具有统计学意义。我们提出，Myc 调节的脂肪酸合成是治疗和/或预防前列腺癌的有效靶点。
