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

  1. Author:
    Maimouni, Sara
    Lee, Mi-Hye
    Sung, You-Me
    Hall, Michael
    Roy, Arpita
    Ouaari, Chokri
    Hwang,Yoo-Seok
    Spivak, Justin
    Glasgow, Eric
    Swift, Matthew
    Patel, Jay
    Cheema, Amrita
    Kumar, Deepak
    Byers, Stephen

  2. Author Address

    Department of Biochemical, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA., Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA., University of the District of Columbia, Washington, DC, USA., Cancer & Developmental Biology Laboratory, National Cancer Institute-Frederick, Frederick, MD, USA.,
    1. Year: 2019
    2. Date: Feb 26
    3. Epub Date: 2019 02 26
  2. Journal: Oncotarget
    1. 10
    2. 17
    3. Pages: 1606-1624
  4. Type of Article: Article
  1. Abstract:

    RARRES1, a retinoic acid regulated carboxypeptidase inhibitor associated with fatty acid metabolism, stem cell differentiation and tumorigenesis is among the most commonly methylated loci in multiple cancers but has no known mechanism of action. Here we show that RARRES1 interaction with cytoplasmic carboxypeptidase 2 (CCP2) inhibits tubulin deglutamylation, which in turn regulates the mitochondrial voltage dependent anion channel (VDAC1), mitochondrial membrane potential, AMPK activation, energy balance and metabolically reprograms cells and zebrafish to a more energetic and anabolic phenotype. Depletion of RARRES1 also increases expression of stem cell markers, promotes anoikis, anchorage independent growth and insensitivity to multiple apoptotic stimuli. As depletion of CCP2 or inhibition of VDAC1 reverses the effects of RARRES1 depletion on energy balance and cell survival we conclude that RARRES1 modulation of CCP2-modulated tubulin-mitochondrial VDAC1 interactions is a fundamental regulator of cancer and stem cell metabolism and survival.

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External Sources

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  2. DOI: 10.18632/oncotarget.26600
  3. PMID: 30899431
  4. PMCID: PMC6422194
  5. PII : 26600

Library Notes

  1. Fiscal Year: FY2018-2019
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