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

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.

Tumor suppressor RARRES1 links tubulin deglutamylation to mitochondrial metabolism and cell survival

“…We monitored the glycolytic shift that occurs following inhibition of mitochondrial respiration, a phenomenon called glycolytic capacity or compensatory glycolysis. Uncoupling respiration with oligomycin increased the ECAR indicating an improved glycolytic capacity in RARRES1 knockdown cells, as observed in our previous study [20]. The opposite is seen in CCP2 depleted cells (Figure 5A).…”

“…Taken together with its effects on apoptosis shown here and elsewhere, these data point to a role for RARRES1-mediated changes in tubulin glutamylation (both C-terminal and side chain) in the general regulation of metabolism and mitochondrial function. Consistent with this possibility are studies that show that RARRES1 and post-translational modification of tubulin can regulate lipid metabolism and the transport of lipid droplets to the mitochondria respectively [20, 47, 48]. Importantly, biophysical studies show a marked effect of BSA conjugated to tubulin-like C-terminal peptides on the activity of the mitochondrial voltage dependent anion channel (VDAC), an important regulator of mitochondrial-dependent cell death, and mitochondrial membrane potential.…”

“…Several studies have pointed to an association of glutamylated tubulin, tubulin glutamylases (TTLLs) and the CCP2 product ∆2-tubulin with cancer and resistance to treatment, but the molecular mechanism(s) or the result of these associations is completely unknown [ 23 , 24 ]. In other studies we showed that RARRES1 controls fatty acid and glucose metabolism by regulating the switch from aerobic glycolysis to glucose dependent de novo lipogenesis [ 20 ]. Taken together with its effects on apoptosis shown here and elsewhere, these data point to a role for RARRES1-mediated changes in tubulin glutamylation (both C-terminal and side chain) in the general regulation of metabolism and mitochondrial function.…”

“…Both RARRES1 and CCP2 have been associated with metabolic diseases and several studies have identified them as important regulators of autophagy [ 14 - 19 ]. We recently identified RARRES1 as a novel regulator of fatty acid metabolism [ 20 ]. CCP2 is a member of the CCP family of deglutamylases important for the removal of glutamic acid residues from the C-terminal tail of several tubulin isoforms [ 21 - 24 ].…”

Early changes in tear film protein profiles after femtosecond LASIK surgery

“…According to our results, particularly the amount of correction had an effect on the expression levels and expression level changes of some proteins. RARRES1 and APOB, both connected to peroxisome proliferating activating receptor (PPAR) and fatty acid metabolism [ 42 , 43 ], had greater decreases in expression levels 1 month after surgery in connection to larger amount of correction. Interestingly, since the different PPAR isoforms have been connected to inflammation and wound healing of cornea, their antagonists have been suggested as potential therapeutic targets in corneal wound healing [ 44 – 46 ].…”