Mitochondria provide the front-line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein, NKX3.1, suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically-engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein, HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function.
Cancer discovery. 2021 Apr 23 [Epub ahead of print]
Alexandros Papachristodoulou, Antonio Rodriguez-Calero, Sukanya Panja, Elizabeth Margolskee, Renu K Virk, Teresa A Milner, Luis Pina Martina, Jaime Y Kim, Matteo Di Bernardo, Alanna B Williams, Elvis A Maliza, Joseph M Caputo, Christopher Haas, Vinson Wang, Guarionex Joel De Castro, Sven Wenske, Hanina Hibshoosh, James M McKiernan, Michael M Shen, Mark A Rubin, Antonina Mitrofanova, Aditya Dutta, Cory Abate-Shen
Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center., Department of Biomedical Research, University of Bern., Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences., Department of Pathology and Cell Biology, Columbia University Irving Medical Center., Feil Family Brain and Mind Research Institute, Weill Cornell Medicine., Departments of Molecular Pharmacology and Therapeutics, Urology, Columbia University Irving Medical Center., Department of Pharmacology, Columbia University Irving Medical Center., Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center., Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center., Department of Urology, Columbia University Irving Medical Center., Herbert Irving Comprehensive Cancer Center, Columbia University., Department of Urology, Columbia University., Medicine, Genetics & Development, Urology, and Systems Biology, Columbia University Medical Center., Department for BioMedical Research, University of Bern., Rutgers Cancer Institute of New Jersey, NJ., Departments of Molecular Pharmacology and Therapeutics, Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center., Departments of Molecular Pharmacology and Therapeutics, Pathology and Cell Biology, Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center .