Epigenetic control of the ubiquitin carboxyl terminal hydrolase 1 in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Cross-Platform Array Screening Identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as Genes Frequently Silenced by Methylation in Melanoma

Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. By integrating gene expression and methylation array analysis we identified novel candidate genes frequently methylated in melanoma. We validated the methylation status of the most promising genes using highly sensitive Sequenom Epityper assays in a large panel of melanoma cell lines and resected melanomas, and compared the findings with those from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. For THBS1 and UCHL1 the effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and future research designed to understand how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis

Zinc homeostasis and signaling in health and diseases: Zinc signaling

The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn’s dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis