Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

Abstract

Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1b (HNF1b), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2 0 deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4a, a transcriptional target of HNF1b, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.

Genetic and functional analyses implicate the NUDT11 , HNF1B , and SLC22A3 genes in prostate cancer pathogenesis

“…HNF1B is a transcription factor that plays a role in kidney and pancreas development (31,32). Mutations of HNF1B have been described in renal cell carcinoma (33), and epigenetic silencing of the gene has been reported in ovarian cancer, as well as gastric, pancreatic, and colorectal cell lines (34). GWAS have implicated variants in the HNF1B locus in diabetes and endometrial cancer risk (35,36).…”

HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes

“…We speculated that the main function of individual gene and genetically synergistic interactions could be the underlying molecular background of diseases. Growing evidence has demonstrated the carcinogenic character of HNF1b in a number of cancers, including those of the endometrium, ovary, kidney, breast, and prostate (Terasawa et al, 2006;Tommasi et al, 2009;Harries et al, 2010;Szponar et al, 2011;Setiawan et al, 2012). To the best of our knowledge, the underlying mechanism of HNF1b for prostate cancer has still been poorly investigated.…”

MicroRNA profiling differentiates colorectal cancer according to KRAS status

“…RGS3, a member of the family regulating G-protein signaling (RGS), strongly promotes apoptosis, when it is up-regulated (Nishiura et al, 2009). Epigenetic inactivation of HNF1B occurs in colorectal cell lines (Terasawa et al, 2006). Down-regulation or loss of expression of HNF1B is correlated with malignant transformation and dedifferentiation (Buchner et al, 2010).…”