title: Degradation of AMPK by a cancer-specific ubiquitin ligase.
abstract: AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.
authors: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Carlos T
authors: CT
authors: Pineda
authors: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Saumya
authors: S
authors: Ramanathan
authors: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Klementina
authors: K
authors: Fon Tacer
authors: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Jenny L
authors: JL
authors: Weon
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Malia B
authors: MB
authors: Potts
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Yi-Hung
authors: YH
authors: Ou
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Michael A
authors: MA
authors: White
authors: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ryan.potts@utsouthwestern.edu.
authors: Patrick Ryan
authors: PR
authors: Potts
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C072013:MAGEA3 protein, human; C000596670:MAGEA3 protein, mouse; C095203:MAGEA6 protein, human; C000596669:MAGEA6 protein, mouse; D009363:Neoplasm Proteins; D055372:AMP-Activated Protein Kinases