Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

Eric J Devor; Brandon M Schickling; Henry D Reyes; Akshaya Warrier; Brittany Lindsay; Michael J Goodheart; Donna A Santillan; Kimberly K Leslie

doi:10.3892/or.2016.4605

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Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

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Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

Eric J Devor, Brandon M Schickling, Henry D Reyes, Akshaya Warrier, Brittany Lindsay, Michael J Goodheart, Donna A Santillan and Kimberly K Leslie

Oncology reports, Vol.35(4), pp.2461-2465

04/2016

DOI: 10.3892/or.2016.4605

PMCID: PMC4774736

PMID: 26847831

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Abstract

Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (-4.3-fold) than the less aggressive endometrioid type (-2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.

Promoter Regions, Genetic

Carcinoma, Endometrioid - genetics

Cell Proliferation

Signal Transduction

Down-Regulation

Humans

Endometrial Neoplasms - metabolism

Gene Expression Regulation, Neoplastic

Carcinoma, Endometrioid - metabolism

Cullin Proteins - genetics

DNA Methylation

Endometrial Neoplasms - genetics

Cell Line, Tumor

Cullin Proteins - metabolism

Endometrial Neoplasms - pathology

Female

MicroRNAs - genetics

3' Untranslated Regions

Carcinoma, Endometrioid - pathology

Details

Title: Subtitle: Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182
Creators: Eric J Devor - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Brandon M Schickling - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Henry D Reyes - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Akshaya Warrier - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Brittany Lindsay - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Michael J Goodheart - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Donna A Santillan - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Kimberly K Leslie - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Oncology reports, Vol.35(4), pp.2461-2465
Publisher: Greece
DOI: 10.3892/or.2016.4605
PMID: 26847831
PMCID: PMC4774736
ISSN: 1021-335X
eISSN: 1791-2431
Grant note: R01 CA099908 / NCI NIH HHS K12 HD000849 / NICHD NIH HHS K12HD000849 / NICHD NIH HHS R01CA99908 / NCI NIH HHS R01 CA184101 / NCI NIH HHS K12 HD063117 / NICHD NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 04/2016
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9983931746302771

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