A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy.
UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth, and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2, suggesting the UBE2O-AMPKα2 axis as a potential cancer therapeutic target.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Isabelle K
IK
Vila
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yixin
Y
Yao
Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do 31151, Republic of Korea.
Goeun
G
Kim
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Weiya
W
Xia
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hyejin
H
Kim
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sun-Joong
SJ
Kim
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mi-Kyung
MK
Park
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
James P
JP
Hwang
Department of Clinical Oncology, Hospital Universitario Morales Meseguer, Murcia 30008, Spain.
Enrique
E
González-Billalabeitia
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
Mien-Chie
MC
Hung
Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do 31151, Republic of Korea. Electronic address: ssong1@sch.ac.kr.
Su Jung
SJ
Song
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: msong1@mdanderson.org.
Min Sup
MS
Song
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D054875:Ubiquitination
D000951:Antigens, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D044763:Ubiquitin-Conjugating Enzymes; C000589772:UBE2O protein, human; C526181:PRKAA2 protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
AMPK; AMPKα2; HIF1α; UBE2O; arsenite; breast cancer; cancer metabolism; mTOR; prostate cancer; ubiquitination