4.8 Article

High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis

Journal

CANCER RESEARCH
Volume 78, Issue 13, Pages 3432-3444

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3018

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Funding

  1. Associazione Italiana per la Ricerca sul Cancro (AIRC Investigator Grant) [15180, 14404, MCO 10.000]
  2. Fondo Ricerca Locale 2017 (University of Turin)
  3. MIUR (the Italian Ministry of University and Scientific Research)
  4. Monzino Foundation
  5. FPRC 5xmille Ministero Salute
  6. Cancer UK

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USP6NL, also named RN-tre, is a GTPase-activating protein involved in controlof endocytosis and signal transduction. Here we report that USP6NL is over-expressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation. Significance: USP6NL overexpression leads to glycolysis addiction of breast cancer cells and presents a point of metabolic vulnerability for therapeutic targeting in a subset of aggressive basal-like breast tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3432/F1.large.jpg.

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