Document Detail

Methylation of the PTPRO gene in human hepatocellular carcinoma and identification of VCP as its substrate.
MedLine Citation:
PMID:  23533167     Owner:  NLM     Status:  MEDLINE    
We have previously reported that the gene encoding protein tyrosine phosphatase receptor type-O (PTPRO) is suppressed by promoter methylation in a rat model of hepatocellular carcinoma (HCC) and it functions as tumor suppressor in leukemia and lung cancer. Here, we explored the methylation and expression of PTPRO as well as its function in human HCC. MassARRAY analysis of primary human HCC and matching liver samples (n = 24) revealed significantly higher (P = 0.004) methylation density at the promoter CGI in tumors. Combined bisulfite restriction analysis (COBRA) of another set of human HCC samples (n = 17) demonstrated that the CGI was methylated in 29% of tumors where expression of PTPRO was lower than that in corresponding matching livers. A substrate-trapping mutant of PTPRO that stabilizes the bound substrates was used to identify its novel substrate(s). VCP/p97 was found to be a PTPRO substrate by mass spectrometry of the peptides pulled down by the substrate-trapping mutant of PTPRO. Tyrosyl dephosphorylation of VCP following ectopic expression of wild-type PTPRO in H293T and HepG2 cells confirmed that it is a bona fide substrate of PTPRO. Treatment of PTPRO overexpressing HepG2 cells with Doxorubicin, a DNA damaging drug commonly used in therapy of primary HCC, sensitized these cells to this potent anticancer drug that correlated with dephosphorylation of VCP. Taken together, these results demonstrate methylation and downregulation of PTPRO in a subset of primary human HCC and establish VCP as a novel functionally important substrate of this tyrosine phosphatase that could be a potential molecular target for HCC therapy.
Shu-hao Hsu; Tasneem Motiwala; Satavisha Roy; Rainer Claus; Mufaddal Mustafa; Christoph Plass; Michael A Freitas; Kalpana Ghoshal; Samson T Jacob
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cellular biochemistry     Volume:  114     ISSN:  1097-4644     ISO Abbreviation:  J. Cell. Biochem.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2013-11-01     Revised Date:  2014-10-19    
Medline Journal Info:
Nlm Unique ID:  8205768     Medline TA:  J Cell Biochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1810-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
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MeSH Terms
Adenosine Triphosphatases / biosynthesis*
Antibiotics, Antineoplastic / pharmacology
Carcinoma, Hepatocellular / drug therapy,  metabolism*,  pathology
Cell Cycle Proteins / biosynthesis*
DNA Methylation*
DNA, Neoplasm / metabolism*
Down-Regulation / drug effects
Doxorubicin / pharmacology
Genes, Neoplasm*
Hep G2 Cells
Liver Neoplasms / metabolism*,  pathology
Receptor-Like Protein Tyrosine Phosphatases, Class 3 / biosynthesis*
Tumor Suppressor Proteins / biosynthesis*
Grant Support
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Cell Cycle Proteins; 0/DNA, Neoplasm; 0/Tumor Suppressor Proteins; 80168379AG/Doxorubicin; EC protein, human; EC Protein Tyrosine Phosphatases, Class 3; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/CDC48 protein

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