Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer

Alison K Esser; Michael R Miller; Qin Huang; Melissa M Meier; Daniel Beltran-Valero de Bernabé; Christopher S Stipp; Kevin P Campbell; Charles F Lynch; Brian J Smith; Michael B Cohen; Michael D Henry

doi:10.1074/jbc.M112.432807

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Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer

Journal article

Open access

Peer reviewed

Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer

Alison K Esser, Michael R Miller, Qin Huang, Melissa M Meier, Daniel Beltran-Valero de Bernabé, Christopher S Stipp, Kevin P Campbell, Charles F Lynch, Brian J Smith, Michael B Cohen, …

The Journal of biological chemistry, Vol.288(4), pp.2132-2142

01/25/2013

DOI: 10.1074/jbc.M112.432807

PMCID: PMC3554886

PMID: 23223448

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Abstract

Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues. Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear. Here, we show that the level of expression of the βDG subunit as well as the glycosylation status of the αDG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of αDG is substantially reduced in prostate cancer metastases. Additionally, we demonstrate that LARGE2 (GYLTL1B), a gene not previously implicated in cancer, regulates functional αDG glycosylation in prostate cancer cell lines; knockdown of LARGE2 resulted in hypoglycosylation of αDG and loss of its ability to bind laminin-111 while overexpression restored ligand binding and diminished growth and migration of an aggressive prostate cancer cell line. Finally, our analysis of LARGE2 expression in human cancer specimens reveals that LARGE2 is significantly down-regulated in the context of prostate cancer, and that its reduction correlates with disease progression. Our results describe a novel molecular mechanism to account for the commonly observed hypoglycosylation of αDG in prostate cancer.

Prostatic Neoplasms - metabolism

Cell Proliferation

Epithelium - metabolism

Cell Separation

Glycosyltransferases - physiology

Membrane Proteins - genetics

Neoplasm Invasiveness

Humans

Gene Expression Regulation, Neoplastic

Extracellular Matrix - metabolism

Male

Glycosylation

Disease Progression

Immunohistochemistry - methods

Flow Cytometry

Microscopy, Fluorescence - methods

Membrane Proteins - physiology

Cell Line, Tumor

Dystroglycans - genetics

Glycosyltransferases - genetics

Laminin - metabolism

Dystroglycans - physiology

Cell Movement

RNA, Small Interfering - metabolism

Details

Title: Subtitle: Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer
Creators: Alison K Esser - Department of Molecular Physiology and Biophysics, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Michael R Miller
Qin Huang
Melissa M Meier
Daniel Beltran-Valero de Bernabé
Christopher S Stipp
Kevin P Campbell
Charles F Lynch
Brian J Smith
Michael B Cohen
Michael D Henry
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(4), pp.2132-2142
DOI: 10.1074/jbc.M112.432807
PMID: 23223448
PMCID: PMC3554886
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: T32 GM067795 / NIGMS NIH HHS P30 ES005605 / NIEHS NIH HHS Howard Hughes Medical Institute T32 GM007337 / NIGMS NIH HHS R01 CA136664 / NCI NIH HHS P50 CA097186 / NCI NIH HHS HHSN261201000032C / PHS HHS P30 CA086862 / NCI NIH HHS R01 CA130916 / NCI NIH HHS T32 CA113275 / NCI NIH HHS R01CA130916 / NCI NIH HHS HHSN261201000032C / NCI NIH HHS CA097186 / NCI NIH HHS
Language: English
Date published: 01/25/2013
Academic Unit: Neurology; Molecular Physiology and Biophysics; Epidemiology; Pathology; Iowa Neuroscience Institute; Biostatistics; Biology; Radiation Oncology; Urology; Holden Comprehensive Cancer Center
Record Identifier: 9983992073202771

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