A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

Isabelle Vila, Yixin Yao, Goeun Kim, Weiya Xia, Hyejin Kim, Sun Joong Kim, Mikyung Park, James P. Hwang, Enrique González-Billalabeitia, Mien-Chie Hung, Su Jung Song, Min Sup Song

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)208-224
Number of pages17
JournalCancer cell
Volume31
Issue number2
DOIs
StatePublished - Feb 13 2017

Fingerprint

Neoplasms
Carcinogenesis
Therapeutics
Ubiquitination
Sirolimus
Pharmacology
Neoplasm Metastasis
Growth
Cellular Reprogramming

Keywords

  • AMPK
  • AMPKα2
  • HIF1α
  • UBE2O
  • arsenite
  • breast cancer
  • cancer metabolism
  • mTOR
  • prostate cancer
  • ubiquitination

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy. / Vila, Isabelle; Yao, Yixin; Kim, Goeun; Xia, Weiya; Kim, Hyejin; Kim, Sun Joong; Park, Mikyung; Hwang, James P.; González-Billalabeitia, Enrique; Hung, Mien-Chie; Song, Su Jung; Song, Min Sup.

In: Cancer cell, Vol. 31, No. 2, 13.02.2017, p. 208-224.

Research output: Contribution to journalArticle

Vila, Isabelle ; Yao, Yixin ; Kim, Goeun ; Xia, Weiya ; Kim, Hyejin ; Kim, Sun Joong ; Park, Mikyung ; Hwang, James P. ; González-Billalabeitia, Enrique ; Hung, Mien-Chie ; Song, Su Jung ; Song, Min Sup. / A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy. In: Cancer cell. 2017 ; Vol. 31, No. 2. pp. 208-224.
@article{74cf766895d44654a0c7305a1d3d4d49,
title = "A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy",
abstract = "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.",
keywords = "AMPK, AMPKα2, HIF1α, UBE2O, arsenite, breast cancer, cancer metabolism, mTOR, prostate cancer, ubiquitination",
author = "Isabelle Vila and Yixin Yao and Goeun Kim and Weiya Xia and Hyejin Kim and Kim, {Sun Joong} and Mikyung Park and Hwang, {James P.} and Enrique Gonz{\'a}lez-Billalabeitia and Mien-Chie Hung and Song, {Su Jung} and Song, {Min Sup}",
year = "2017",
month = "2",
day = "13",
doi = "10.1016/j.ccell.2017.01.003",
language = "English (US)",
volume = "31",
pages = "208--224",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

AU - Vila, Isabelle

AU - Yao, Yixin

AU - Kim, Goeun

AU - Xia, Weiya

AU - Kim, Hyejin

AU - Kim, Sun Joong

AU - Park, Mikyung

AU - Hwang, James P.

AU - González-Billalabeitia, Enrique

AU - Hung, Mien-Chie

AU - Song, Su Jung

AU - Song, Min Sup

PY - 2017/2/13

Y1 - 2017/2/13

N2 - 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.

AB - 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.

KW - AMPK

KW - AMPKα2

KW - HIF1α

KW - UBE2O

KW - arsenite

KW - breast cancer

KW - cancer metabolism

KW - mTOR

KW - prostate cancer

KW - ubiquitination

UR - http://www.scopus.com/inward/record.url?scp=85011269383&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011269383&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.01.003

DO - 10.1016/j.ccell.2017.01.003

M3 - Article

C2 - 28162974

AN - SCOPUS:85011269383

VL - 31

SP - 208

EP - 224

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 2

ER -