NADK-mediated de novo NADP(H) synthesis is a metabolic adaptation essential for breast cancer metastasis
Didem Ilter,
Stanislav Drapela,
Tanya Schild,
Nathan P. Ward,
Emma Adhikari,
Vivien Low,
John Asara,
Thordur Oskarsson,
Eric K. Lau,
Gina M. DeNicola,
Melanie R. McReynolds,
Ana P. Gomes
Affiliations
Didem Ilter
Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Stanislav Drapela
Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Tanya Schild
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Nathan P. Ward
Department of Cancer Physiology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Emma Adhikari
Department of Tumor Biology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Vivien Low
Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
John Asara
Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA, USA
Thordur Oskarsson
Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Eric K. Lau
Department of Tumor Biology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Gina M. DeNicola
Department of Cancer Physiology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA
Melanie R. McReynolds
Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA, USA; Huck Institutes of the Life Sciences, Penn State University, University Park, PA, USA
Ana P. Gomes
Department of Molecular Oncology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, USA; Corresponding author.
Metabolic reprogramming and metabolic plasticity allow cancer cells to fine-tune their metabolism and adapt to the ever-changing environments of the metastatic cascade, for which lipid metabolism and oxidative stress are of particular importance. NADPH is a central co-factor for both lipid and redox homeostasis, suggesting that cancer cells may require larger pools of NADPH to efficiently metastasize. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells; however, de novo NADP+ is synthesized only through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). Here, we show that NADK is upregulated in metastatic breast cancer cells enabling de novo production of NADP(H) and the expansion of the NADP(H) pools thereby increasing the ability of these cells to adapt to the challenges of the metastatic cascade and efficiently metastasize. Mechanistically, we found that metastatic signals lead to a histone H3.3 variant-mediated epigenetic regulation of the NADK promoter, resulting in increased NADK levels in cells with metastatic ability. Together, our work presents a previously uncharacterized role for NADK and de novo NADP(H) production as a contributor to breast cancer progression and suggests that NADK constitutes an important and much needed therapeutic target for metastatic breast cancers.
