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

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

doi:10.1016/j.ccell.2017.01.003

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

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

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

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 language	English (US)
Pages (from-to)	208-224
Number of pages	17
Journal	Cancer cell
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2017.01.003
State	Published - Feb 13 2017

Keywords

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

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Genetically Engineered Mouse Facility
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource

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10.1016/j.ccell.2017.01.003

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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 = "Vila, {Isabelle K.} and Yixin Yao and Goeun Kim and Weiya Xia and Hyejin Kim and Kim, {Sun Joong} and Park, {Mi Kyung} and Hwang, {James P.} and Enrique Gonz{\'a}lez-Billalabeitia and Hung, {Mien Chie} and Song, {Su Jung} and Song, {Min Sup}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = feb,

day = "13",

doi = "10.1016/j.ccell.2017.01.003",

language = "English (US)",

volume = "31",

pages = "208--224",

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

AU - Vila, Isabelle K.

AU - Yao, Yixin

AU - Kim, Goeun

AU - Xia, Weiya

AU - Kim, Hyejin

AU - Kim, Sun Joong

AU - Park, Mi Kyung

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

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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