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

Sara Maimouni,Naiem Issa,Deepak Kumar,Stephen Byers,Chokri Ouaari,Selina Cheng,Amrita Cheema,Ming Tan

doi:10.1371/journal.pone.0208756

Abstract

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.

Highlights

Retinoic acid receptor responder element 1 (RARRES1), known as tazarotene induced gene 1 (TIG1), was initially identified as a novel retinoic acid receptor-regulated gene in the skin [1]
We showed in prostate cancer cells that RARRES1 is able to induce autophagy, decrease mechanistic target of rapamycin and increase Sirtuin 1 (SIRT1), two important regulators of energy homeostasis [2]
Since RARRES1 expression is associated with metabolism-associated diseases and its exogenous expression regulates the expression of two important players in metabolic reprogramming [2], we examined whether RARRES1 has any functional significance in metabolic reprogramming

Summary

Introduction

Retinoic acid receptor responder element 1 (RARRES1), known as tazarotene induced gene 1 (TIG1), was initially identified as a novel retinoic acid receptor-regulated gene in the skin [1]. We showed in prostate cancer cells that RARRES1 is able to induce autophagy, decrease mechanistic target of rapamycin (mTOR) and increase Sirtuin 1 (SIRT1), two important regulators of energy homeostasis [2]. RARRES1 induces autophagy in cervical cancer cells [3]. The ability of RARRES1 to regulate the expression of metabolic master regulators and induce autophagy suggests that it might function to reprogram metabolism in cells.

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Conclusion