Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT
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Justyna Kanska1, Paul-Joseph P. Aspuria1, Barbie Taylor-Harding1, Lindsay Spurka2, Vincent Funari2, Sandra Orsulic1,3, Beth Y. Karlan1,3, W. Ruprecht Wiedemeyer1,3
1Women’s Cancer Program at the Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
2Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
3Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA 90048, USA
W. Ruprecht Wiedemeyer, email: firstname.lastname@example.org
Keywords: nicotinamide N-methyltransferase, ovarian cancer, chronic nutritional stress, mesenchymal gene expression, cancer metabolism
Received: July 20, 2016 Accepted: February 06, 2017 Published: February 17, 2017
Glucose is considered the primary energy source for all cells, and some cancers are addicted to glucose. Here, we investigated the functional consequences of chronic glucose deprivation in serous ovarian cancer cells. We found that cells resistant to glucose starvation (glucose-restricted cells) demonstrated increased metabolic plasticity that was dependent on NNMT (Nicotinamide N-methyltransferase) expression. We further show that ZEB1 induced NNMT, rendered cells resistant to glucose deprivation and recapitulated metabolic adaptations and mesenchymal gene expression observed in glucose-restricted cells. NNMT depletion reversed metabolic plasticity in glucose-restricted cells and prevented de novo formation of glucose-restricted colonies. In addition to its role in glucose independence, we found that NNMT was required for other ZEB1-induced phenotypes, such as increased migration. NNMT protein levels were also elevated in metastatic and recurrent tumors compared to matched primary carcinomas, while normal ovary and fallopian tube tissue had no detectable NNMT expression. Our studies define a novel ZEB1/NNMT signaling axis, which elicits mesenchymal gene expression, as well as phenotypic and metabolic plasticity in ovarian cancer cells upon chronic glucose starvation. Understanding the causes of cancer cell plasticity is crucial for the development of therapeutic strategies to counter intratumoral heterogeneity, acquired drug resistance and recurrence in high-grade serous ovarian cancer (HGSC).
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