Tumor suppressor RARRES1- A novel regulator of fatty acid metabolism in epithelial cells

• Published in: PloS one 2018-12, Vol.13 (12), p.e0208756-e0208756
• Main Authors: Maimouni, Sara, Issa, Naiem, Cheng, Selina, Ouaari, Chokri, Cheema, Amrita, Kumar, Deepak, Byers, Stephen
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Autophagy; Binding sites; Biology and Life Sciences; Breast - metabolism; Breast cancer; Breast Neoplasms - metabolism; Cell Line; Cellular biology; Cloning; Colorectal Neoplasms - metabolism; Depletion; Electron transport; Epithelial cells; Epithelial Cells - metabolism; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - metabolism; Fatty acids; Fatty Acids - metabolism; Fatty liver; Fatty-acid synthase; Gene Expression; Genomics; Glucose; Glucose - metabolism; Glycolysis; Glycolysis - physiology; Health aspects; Humans; Hyperinsulinemia; Kinases; Lipid Metabolism - physiology; Lipids; Lipogenesis; Lipogenesis - physiology; Liver; Liver diseases; Male; Medicine and Health Sciences; Membrane Proteins - metabolism; Metabolism; Mitochondria; Oncology; Oxidation; Oxidation-Reduction; Peroxisome proliferator-activated receptors; Physical Sciences; Prostate; Prostate - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Retinoic acid; Solid tumors; Steatosis; Transcription factors; Tumor suppressor genes; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0208756

Retinoic acid receptor responder 1 (RARRES1) is silenced in many cancers and is differentially expressed in metabolism associated diseases, such as hepatic steatosis, hyperinsulinemia and obesity. Here we report a novel function of RARRES1 in metabolic reprogramming of epithelial cells. Using non-targeted LC-MS, we discovered that RARRES1 depletion in epithelial cells caused a global increase in lipid synthesis. RARRES1-depleted cells rewire glucose metabolism by switching from aerobic glycolysis to glucose-dependent de novo lipogenesis (DNL). Treatment with fatty acid synthase (FASN) inhibitor, C75, reversed the effects of RARRES1 depletion. The increased DNL in RARRES1-depleted normal breast and prostate epithelial cells proved advantageous to the cells during starvation, as the increase in fatty acid availability lead to more oxidized fatty acids (FAO), which were used for mitochondrial respiration. Expression of RARRES1 in several common solid tumors is also contextually correlated with expression of fatty acid metabolism genes and fatty acid-regulated transcription factors. Pathway enrichment analysis led us to determine that RARRES1 is regulated by peroxisome proliferating activated receptor (PPAR) signaling. These findings open up a new avenue for metabolic reprogramming and identify RARRES1 as a potential target for cancers and other diseases with impaired fatty acid metabolism.