Epigenetic control of the ubiquitin carboxyl terminal hydrolase 1 in renal cell carcinoma.
BACKGROUND
The ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) gene involved in the regulation of cellular ubiquitin levels plays an important role in different cellular processes including cell growth and differentiation. Aberrant expression of UCHL1 has been found in a number of human solid tumors including renal cell carcinoma (RCC). In RCC, UCHL1 overexpression is associated with tumor progression and an altered von Hippel Lindau gene expression.


METHODS
To determine the underlying mechanisms for the heterogeneous UCHL1 expression pattern in RCC the UCHL1 promoter DNA methylation status was determined in 17 RCC cell lines as well as in 32 RCC lesions and corresponding tumor adjacent kidney epithelium using combined bisulfite restriction analysis as well as bisulfite DNA sequencing.


RESULTS
UCHL1 expression was found in all 32 tumor adjacent kidney epithelium samples. However, the lack of or reduced UCHL1 mRNA and/or protein expression was detected in 13/32 RCC biopsies and 7/17 RCC cell lines and due to either a total or partial methylation of the UCHL1 promoter DNA. Upon 2'-deoxy-5-azacytidine treatment an induction of UCHL1 mRNA and protein expression was found in 9/17 RCC cell lines, which was linked to the demethylation degree of the UCHL1 promoter DNA.


CONCLUSIONS
Promoter hypermethylation represents a mechanism for the silencing of the UCHL1 gene expression in RCC and supports the concept of an epigenetic control for the expression of UCHL1 during disease progression.
Martin Luther University Halle-Wittenberg, Institute of Medical Immunology, Halle, Germany. Barbara.Seliger@medizin.uni-halle.de
Barbara
B
Seliger
Diana
D
Handke
Elisabeth
E
Schabel
Juergen
J
Bukur
Rudolf
R
Lichtenfels
Reinhard
R
Dammann
D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase