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

Abstract

USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed 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. Cancer Res; 78(13); 3432–44. ©2018 AACR.

S100A2 promotes glycolysis and proliferation via GLUT1 regulation in colorectal cancer

“…GLUT1, a major glucose transporter protein, was upregulated in various tumor cells. 43,44 It should be noted that significantly reduced concentrations of glucose were observed in S100A2 knockout cells, whereas S100A2 overexpression cells exhibited higher levels than controls. In this study, we also proved that inhibited GLUT1 could abrogate S100A2-enhanced proliferation and glycolysis in colorectal cancer cells.…”

Metabolic Reprogramming in Triple-Negative Breast Cancer

“…GLUT1 overexpression is significantly correlated with TNBC, and it promotes TNBC cell proliferation and invasion (38,39). Notably, serine/threonine kinase AKT stabilizes GLUT1 at the cell membrane by perturbing its endocytosis, therefore promoting aerobic glycolysis (41).…”

“…USP6NL, a GTPase-activating protein involved in signal transduction regulation, is often overexpressed in basal-like TNBC. Knockdown of USP6NL impairs epidermal growth factor receptor (EGFR)/AKT signaling and promotes GLUT1 degradation, thus suspending cell proliferation exclusively in aggressive basal-like TNBC tumors harboring USP6NL overexpression (41).…”

A semi-supervised Bayesian approach for simultaneous protein sub-cellular localisation assignment and novelty detection

“…Additionally, Rab5 was shown to participate in adenovirus endocytosis (Rauma et al, 1999), both Rab5a and Rab5b were found to play functional roles in web formation and viral genome replication during HCV (hepatitis C virus) infection (Stone et al, 2007), and Rab5a was identied as a crucial target of HBV (hepatitis B virus) during HBV-related hepatocellular carcinoma pathogenesis (Sheng et al, 2014). been proposed as a potential therapeutic target for these types of breast cancer (Avanzato et al, 2018). This protein also plays a functional role in infection, as it was shown to regulate the uptake and intracellular tracking of Shiga toxins (Fuchs et al, 2007).…”