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

Sara Maimouni1, Mi-Hye Lee2, You-Me Sung2

  • 1Department of Biochemical, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.

Oncotarget
|March 23, 2019
PubMed

Insights

RARRES1 regulates cell metabolism and survival by interacting with CCP2, affecting tubulin and VDAC1. This mechanism is crucial for cancer and stem cell energy balance and growth.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Cancer Research

Background:

  • RARRES1 is a retinoic acid-regulated carboxypeptidase inhibitor implicated in fatty acid metabolism, stem cell differentiation, and tumorigenesis.
  • RARRES1 is frequently methylated in various cancers, yet its precise mechanism of action remains unknown.
  • Understanding RARRES1's function is critical for developing novel cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism of action of RARRES1 in regulating cellular metabolism and survival.
  • To investigate the interaction between RARRES1, cytoplasmic carboxypeptidase 2 (CCP2), and tubulin deglutamylation.
  • To determine the role of RARRES1 in mitochondrial function and its impact on cancer and stem cell phenotypes.

Main Methods:

  • Investigated the interaction between RARRES1 and CCP2 using biochemical assays.
  • Assessed the impact of RARRES1 on tubulin deglutamylation and mitochondrial voltage dependent anion channel 1 (VDAC1) regulation.
  • Utilized cell culture and zebrafish models to study the effects of RARRES1 depletion on energy balance, cell survival, and stem cell markers.
  • Examined the reversal of RARRES1 depletion effects by CCP2 depletion or VDAC1 inhibition.

Main Results:

  • RARRES1 interacts with CCP2, inhibiting tubulin deglutamylation.
  • This inhibition impacts VDAC1, mitochondrial membrane potential, and AMPK activation, leading to metabolic reprogramming towards an anabolic phenotype.
  • RARRES1 depletion increases stem cell markers, promotes anoikis, anchorage-independent growth, and resistance to apoptosis.
  • Depletion of CCP2 or inhibition of VDAC1 reverses the metabolic and survival effects of RARRES1 depletion.

Conclusions:

  • RARRES1 acts as a key regulator of cellular energy balance and survival through its modulation of the CCP2-tubulin-VDAC1 pathway.
  • This pathway is fundamental to the metabolic reprogramming and survival advantages observed in cancer and stem cells.
  • Targeting the RARRES1-CCP2-VDAC1 axis offers potential therapeutic strategies for cancer and stem cell-related diseases.
Keywords:
PTM tubulinRARRES1drug resistancemetabolic reprogrammingretinoic acid signaling

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