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Further Evidence of the Importance of 5-hydroxymethylation in Cancer

The discovery of the “6th base”, 5-hydroxymethylated cytosine, has resulted in rapid fire publication activity.  Researchers are exploring it’s part in demethylation dynamics, and its epigenetic function. Today I wanted to highlight the paper, H. Yang, et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation (March 2012) Oncogene 1-7. It provides further detailed analysis that is complementary to the work described by Hafner et al., please see my Q&A with Dr. Yegnasubramanian. The Oncogene paper research group, mainly out of Fudan University, looked at additional tissue types using an anti-5-hmC antibody for immunolocalization in paraffin embedded samples. They sampled human breast, prostate, liver, lung and pancreas, comparing them with corresponding matched normal surrounding tissues. They also viewed liver and lung tumors in genetically engineered mice models. All of these tumor tissue types had dramatic losses of 5-hmC by immunohistochemistry. The group also briefly noted the inverse correlation of 5-hmC with 5-mC levels. (Remember in the Hafner et al. paper, they showed losses of 5-hmC, independent from 5-mC.) They followed up with a quantitative dot blot hybridization method for 5-hmC, also using paraffin-embedded tissue clinical samples. All their data points to the possible utility of 5-hmC as a broad cancer diagnostic biomarker, based on its tight inverse correlation with tumorigenesis. Of course, as per the title of this paper, there is a final juicy tid bit. They collected mRNA expression data for the three TET genes from frozen human breast and liver cancer samples. Neither of these cancer types have known mutations for the TET genes or the metabolic enzymes, IDH1/2. Yet, all three types of TET expression was “significantly and uniformly reduced” for all samples. That’s good evidence to seek a different upstream demethylation mechanism…

It’s clear there is a story to uncover based on the dynamic and divergent patterns of methylation and hydroxymethylation already demonstrated in cancer. The full demethylation process is still unknown. Since this mark is not distingishable from 5-mC by Bisulfite sequencing there could be a lot of back data to re-analyze, too. Tools for broad 5-hmC analysis include J-binding proteins or anti-5-hmC specific antibodies. Hydroxymethylation dependent restriction enzymes are useful for high resolution studies. Given this new expression information on 5-hmC in human cancers, it’s interesting to ponder its role in development, differentiation, and disease.

Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, & Xiong Y (2012). Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene PMID: 22391558

This entry was posted in Biomarkers, DNA Methylation, Diagnostics, History & Trends, Imaging, Immunohistochemistry, Oncology and tagged , , , , . Bookmark the permalink.

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