HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth
Kurosh Ameri,
Arman Jahangiri,
Anthony M. Rajah,
Kathryn V. Tormos,
Ravi Nagarajan,
Melike Pekmezci,
Vien Nguyen,
Matthew L. Wheeler,
Michael P. Murphy,
Timothy A. Sanders,
Stefanie S. Jeffrey,
Yerem Yeghiazarians,
Paolo F. Rinaudo,
Joseph F. Costello,
Manish K. Aghi,
Emin Maltepe
Affiliations
Kurosh Ameri
Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Arman Jahangiri
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Anthony M. Rajah
Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Kathryn V. Tormos
Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Ravi Nagarajan
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Melike Pekmezci
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
Vien Nguyen
Department of Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Matthew L. Wheeler
Department of Microbiology/Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Michael P. Murphy
Mitochondrial Biology Unit, MRC, Cambridge CB2 0XY, UK
Timothy A. Sanders
Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Stefanie S. Jeffrey
Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Yerem Yeghiazarians
Department of Medicine/CVRI/Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA
Paolo F. Rinaudo
Department of Obstetrics, Gynecology/Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Joseph F. Costello
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Manish K. Aghi
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Emin Maltepe
Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA
Hypoxia-inducible gene domain family member 1A (HIGD1A) is a survival factor induced by hypoxia-inducible factor 1 (HIF-1). HIF-1 regulates many responses to oxygen deprivation, but viable cells within hypoxic perinecrotic solid tumor regions frequently lack HIF-1α. HIGD1A is induced in these HIF-deficient extreme environments and interacts with the mitochondrial electron transport chain to repress oxygen consumption, enhance AMPK activity, and lower cellular ROS levels. Importantly, HIGD1A decreases tumor growth but promotes tumor cell survival in vivo. The human Higd1a gene is located on chromosome 3p22.1, where many tumor suppressor genes reside. Consistent with this, the Higd1a gene promoter is differentially methylated in human cancers, preventing its hypoxic induction. However, when hypoxic tumor cells are confronted with glucose deprivation, DNA methyltransferase activity is inhibited, enabling HIGD1A expression, metabolic adaptation, and possible dormancy induction. Our findings therefore reveal important new roles for this family of mitochondrial proteins in cancer biology.
