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


The cover for issue 17 of Oncotarget features Figure 8, "Schematic diagram of the effects of RARRES1 and CCP2 on post translational modification of tubulin and the mitochondrial voltage dependent anion channel," by Maimouni, et al.

As depletion of CCP2 or inhibition of VDAC1 reverses the effects of RARRES1 depletion on energy balance and cell survival the research team conclude that RARRES1 modulation of CCP2-modulated tubulin-mitochondrial VDAC1 interactions is a fundamental regulator of cancer and stem cell metabolism and survival.

Dr. Stephen Byers from the Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA and the Department of Biochemical, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA said "Cancer cells and stem cells share several common features including similar changes in metabolism and resistance to mitochondria mediated cell death."

With the exception of LKB1, which regulates the cytoplasmic ATP sensor AMPK, no tumor suppressor genes are known to directly regulate glycolysis or mitochondrial metabolic activity.

Figure 1: RARRES1, CCP2 and Retinoic acid Regulate Tubulin Glutamylation.

RARRES1, a retinoic acid regulated tumor suppressor gene associated with ageing, metabolism and stem cell differentiation is among the most commonly methylated loci in multiple cancers but has no known molecular function.

Peptide mimics of the acidic C-terminal tail of tubulin can also directly influence the activity of mitochondrial voltage dependent anion channels and mitochondrial membrane potential, raising the possibility that pathways that alter its acidic C-terminal tail could influence mitochondrial activity directly by influencing VDAC function.

The researchers showed that the metabolic and tumor suppressor effects of RARRES1 are mediated by its inhibition of CCP2 catalyzed tubulin deglutamylation, which in turn regulates mitochondrial bioenergetics and subsequently alters energy homeostasis by modulating the function of the mitochondrial voltage-dependent anion channel 1.

The Byers research team concluded, "Loss of RARRES1 in multiple tumor types, its role in stem cell differentiation and in cell survival indicates that the RARRES1/CCP2 axis could be a candidate for therapeutic intervention. In this study, we were able to successfully reverse the resistant phenotype of RARRES1-depleted cells by treating cells with itraconazole, an anti-fungal drug that inhibits the activity of VDAC in mammalian cells."

Full text - https://doi.org/10.18632/oncotarget.26600

Correspondence to - Stephen Byers - [email protected]

Keywords - retinoic acid signaling, RARRES1, metabolic reprogramming, PTM tubulin, drug resistance

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