UBE1L causes lung cancer growth suppression by targeting cyclin D1

Qing Feng; David Sekula; Yongli Guo; Xi Liu; Candice C Black; Fabrizio Galimberti; Sumit J Shah; Lorenzo F Sempere; Vincent Memoli; Jesper Bøje Andersen; Bret A Hassel; Konstantin Dragnev; Ethan Dmitrovsky

doi:10.1158/1535-7163.MCT-08-0753

UBE1L causes lung cancer growth suppression by targeting cyclin D1

Qing Feng, David Sekula, Yongli Guo, Xi Liu, Candice C Black, Fabrizio Galimberti, Sumit J Shah, Lorenzo F Sempere, Vincent Memoli, Jesper Bøje Andersen, Bret A Hassel, Konstantin Dragnev, Ethan Dmitrovsky

59 Citations (Scopus)

Abstract

UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.

Original language	English
Journal	Molecular Cancer Therapeutics
Volume	7
Issue number	12
Pages (from-to)	3780-8
Number of pages	9
ISSN	1535-7163
DOIs	https://doi.org/10.1158/1535-7163.MCT-08-0753
Publication status	Published - Dec 2008
Externally published	Yes

Keywords

Anticarcinogenic Agents
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cyclin D1
Cycloheximide
Cytokines
Humans
Ki-67 Antigen
Lung Neoplasms
Models, Biological
Plasmids
Retinoid X Receptors
Tetrahydronaphthalenes
Ubiquitin-Activating Enzymes
Ubiquitins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1535-7163.MCT-08-0753

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title = "UBE1L causes lung cancer growth suppression by targeting cyclin D1",

abstract = "UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.",

keywords = "Anticarcinogenic Agents, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Cycloheximide, Cytokines, Humans, Ki-67 Antigen, Lung Neoplasms, Models, Biological, Plasmids, Retinoid X Receptors, Tetrahydronaphthalenes, Ubiquitin-Activating Enzymes, Ubiquitins",

author = "Qing Feng and David Sekula and Yongli Guo and Xi Liu and Black, {Candice C} and Fabrizio Galimberti and Shah, {Sumit J} and Sempere, {Lorenzo F} and Vincent Memoli and Andersen, {Jesper B{\o}je} and Hassel, {Bret A} and Konstantin Dragnev and Ethan Dmitrovsky",

year = "2008",

month = dec,

doi = "10.1158/1535-7163.MCT-08-0753",

language = "English",

volume = "7",

pages = "3780--8",

journal = "Molecular Cancer Therapeutics",

issn = "1535-7163",

publisher = "American Association for Cancer Research (A A C R)",

number = "12",

}

TY - JOUR

T1 - UBE1L causes lung cancer growth suppression by targeting cyclin D1

AU - Feng, Qing

AU - Sekula, David

AU - Guo, Yongli

AU - Liu, Xi

AU - Black, Candice C

AU - Galimberti, Fabrizio

AU - Shah, Sumit J

AU - Sempere, Lorenzo F

AU - Memoli, Vincent

AU - Andersen, Jesper Bøje

AU - Hassel, Bret A

AU - Dragnev, Konstantin

AU - Dmitrovsky, Ethan

PY - 2008/12

Y1 - 2008/12

N2 - UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.

AB - UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.

KW - Anticarcinogenic Agents

KW - Cell Cycle

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cyclin D1

KW - Cycloheximide

KW - Cytokines

KW - Humans

KW - Ki-67 Antigen

KW - Lung Neoplasms

KW - Models, Biological

KW - Plasmids

KW - Retinoid X Receptors

KW - Tetrahydronaphthalenes

KW - Ubiquitin-Activating Enzymes

KW - Ubiquitins

U2 - 10.1158/1535-7163.MCT-08-0753

DO - 10.1158/1535-7163.MCT-08-0753

M3 - Journal article

C2 - 19074853

SN - 1535-7163

VL - 7

SP - 3780

EP - 3788

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 12

ER -

UBE1L causes lung cancer growth suppression by targeting cyclin D1

Abstract

Keywords

UN SDGs

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