Download Epigenetic Down-regulation of Pygo1 and the Activation of Wnt

Epigenetic Down-regulation of Pygo1 and the Activation of Wnt Signaling
Pathway in Bladder Cancer
Speaker: Lin-Chien Hung
Adsivisor: Cheng-Da Hsu ,Michael Wing-Yan Chan
Date: 2010 /06/ 04
Abstract:
Bladder cancer is a common urologic cancer. The most common pathology of bladder
tumors is transitional cell carcinoma (TCC), which begins in cells that normally make up the
inner lining of the bladder. The canonical Wnt/β-Catenin signaling pathway is associated
with the regulation of growth and differentiation events in cells. Previous studies indicated
that WNT signaling pathway has played a pivotal role in tumorgenesis and development of
urothelium. Genetic alternation in components of this pathway, such as APC and β-Catenin,
were infrequent in TCC. Thus we speculate that other alteration in nuclear components of
this pathway may influence the carcinogenesis in TCC. Pygo is a newly identified
Wnt/β-Catenin nuclear component which mediates the transcriptional activity in Drosophila
development. In vertebrates two orthologues, Pygo1 and Pygo2 are identified, but their
functional roles remain unclear in cancer study. Therefore, in this study, we speculate that
WNT signaling pathway is active in TCC cell lines and the alteration of Pygo1 expression
plays a role in the carcinogenesis of TCC. We measured the expression level of cyclin D1
and Dkk1 mRNA which are WNT target genes to determine the activity of Wnt/β-Catenin
signaling pathway in TCC cell lines. Our data shows that the mRNA expression level of
these two genes among TCC cell lines was significantly higher than that of normal bladder
mucosa, indicating a significant Wnt/β-Catenin signaling activation. We also measured the
expression level of Pygo1 mRNA expression in TCC cell lines and showed that pygo1 was
significant down-regulated in TCC cell lines and tumor tissues as compared to normal
control. We speculated that epigenetic regulation such as DNA methylation or Histone
modification might contribute to the down-regulation of pygo1 in TCC. Our pharmacological
data demonstrated that pygo1 gene expression was regulated by DNA methylation.
Subsequently, we confirmed this mechanism and determined the pygo1 promoter
methylation profile by doing bisulfite sequencing. In the future, we will do signal reporter
assay to confirm the WNT activity in TCC cell lines.