Abstract
Epigenetic regulation of gene expression is commonly altered in human cancer. We have observed alterations of DNA methylation and microRNA expression that reflect the biology of bladder cancer. This common disease arises by distinct pathways with low and high-grade differentiation. We hypothesized that epigenetic gene regulation reflects an interaction between histone and DNA modifications, and differences between normal and malignant urothelial cells represent carcinogenic events within bladder cancer. To test this we profiled two repressive histone modifications (H3K9m3 and H3K27m3) using ChIP-Seq, cytosine methylation using MeDIP and mRNA expression in normal and malignant urothelial cell lines. In genes with low expression we identified H3K27m3 and DNA methylation each in 20–30% of genes and both marks in 5% of genes. H3K9m3 was detected in 5–10% of genes but was not associated with overall expression. DNA methylation was more closely related to gene expression in malignant than normal cells. H3K27m3 was the epigenetic mark most specifically correlated to gene silencing. Our data suggest that urothelial carcinogenesis is accompanied by a loss of control of both DNA methylation and H3k27 methylation. From our observations we identified a panel of genes with cancer specific-epigenetic mediated aberrant expression including those with reported carcinogenic functions and members potentially mediating a positive epigenetic feedback loop. Pathway enrichment analysis revealed genes marked by H3K9m3 were involved with cell homeostasis, those marked by H3K27m3 mediated pro-carcinogenic processes and those marked with cytosine methylation were mixed in function. In 150 normal and malignant urothelial samples, our gene panel correctly estimated expression in 65% of its members. Hierarchical clustering revealed that this gene panel stratified samples according to the presence and phenotype of bladder cancer.
Highlights
Bladder cancer is the fifth commonest malignancy in the United States with 70, 530 new cases and 14,680 deaths in 2010 [1]
Histone enrichment in urothelial cells We performed massively parallel sequencing to determine the distribution of DNA adjacent to H3K9m3 and H3K27m3 in urothelial cells
We have produced integrated epigenomic maps for two Urothelial Cell Carcinoma (UCC) cell lines and non-transformed normal urothelial cells. The latter are cultured expansions taken from disease free patients that grow as sheets of histologically normal appearing urothelial cells for 7–8 passages before senescence
Summary
Bladder cancer is the fifth commonest malignancy in the United States with 70, 530 new cases and 14,680 deaths in 2010 [1]. The majority of tumors are Urothelial Cell Carcinoma (UCC). Clinicopathological data suggest this disease arises by two distinct pathways with low and high-grade cellular differentiation. The clinical phenotype and treatment of these two pathways differs considerably and molecular comparisons reveal few common events. The majority of UCC are low-grade tumors, which are characterized by FGFR3 mutation, chromosome 9 loss and relatively few other molecular alterations [2]. High-grade tumors have widespread chromosomal instability, numerous molecular changes and are best characterized by loss of p53 function
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
