title: HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth.
abstract: 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.
authors: Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Kurosh
authors: K
authors: Ameri
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Arman
authors: A
authors: Jahangiri
authors: Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Anthony M
authors: AM
authors: Rajah
authors: Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Kathryn V
authors: KV
authors: Tormos
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Ravi
authors: R
authors: Nagarajan
authors: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Melike
authors: M
authors: Pekmezci
authors: Department of Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Vien
authors: V
authors: Nguyen
authors: Department of Microbiology/Immunology, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Matthew L
authors: ML
authors: Wheeler
authors: Mitochondrial Biology Unit, MRC, Cambridge CB2 0XY, UK.
authors: Michael P
authors: MP
authors: Murphy
authors: Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Timothy A
authors: TA
authors: Sanders
authors: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Stefanie S
authors: SS
authors: Jeffrey
authors: Department of Medicine/CVRI/Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Yerem
authors: Y
authors: Yeghiazarians
authors: Department of Obstetrics, Gynecology/Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Paolo F
authors: PF
authors: Rinaudo
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Joseph F
authors: JF
authors: Costello
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
authors: Manish K
authors: MK
authors: Aghi
authors: Department of Pediatrics/Biomedical Sciences, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: emin.maltepe@ucsf.edu.
authors: Emin
authors: E
authors: Maltepe