Promoter Hypermethylation Mediated Downregulation of FBP1 in Human Hepatocellular Carcinoma and Colon Cancer
Open Access
- 19 October 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (10), e25564
- https://doi.org/10.1371/journal.pone.0025564
Abstract
FBP1, fructose-1,6-bisphosphatase-1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The mechanism that it functions to antagonize glycolysis and was epigenetically inactivated through NF-kappaB pathway in gastric cancer has been reported. However, its role in the liver carcinogenesis still remains unknown. Here, we investigated the expression and DNA methylation of FBP1 in primary HCC and colon tumor. FBP1 was lowly expressed in 80% (8/10) human hepatocellular carcinoma, 66.7% (6/9) liver cancer cell lines and 100% (6/6) colon cancer cell lines, but was higher in paired adjacent non-tumor tissues and immortalized normal cell lines, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCCs, gastric and colon tumor tissues, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 29 CpG sites at a 327-bp promoter region by bisulfite genomic sequencing confirmed its methylation. FBP1 silencing could be reversed by chemical demethylation treatment with 5-aza-2′-deoxycytidine (Aza), indicating direct epigenetic silencing. Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest. Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS) generation. In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer. FBP1 appears to be a functional tumor suppressor involved in the liver and colon carcinogenesis.Keywords
This publication has 13 references indexed in Scilit:
- Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesisOncogene, 2009
- Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivationBiochemical Journal, 2009
- Aberrant methylation of human L- and M-fructose 1,6-bisphosphatase genes in cancerBiochemical and Biophysical Research Communications, 2008
- Redox Regulation of Cell SurvivalAntioxidants and Redox Signaling, 2008
- Reactive Oxygen Species: A Breath of Life or Death?Clinical Cancer Research, 2007
- The Epigenomics of CancerCell, 2007
- Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNAInternational Journal of Cancer, 2006
- Fructose-1,6-bisphosphatase mediates cellular responses to DNA damage and aging in Saccharomyces cerevisiaeMutation Research, 2006
- Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?Nature Reviews Cancer, 2006
- CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter futureOncogene, 2002