Patients with diabetes do not get a sweet deal; the long-term complications associated with high blood sugar levels include cardiovascular disease, stroke, eye damage, kidney disease, and foot ulcers. Additionally, diabetic patients suffer from a higher risk of developing cancer, although quite how prolonged high blood sugar levels drives genetic and/or epigenetic alterations towards tumorigenesis remains undescribed.
Researchers from the lab of Yujiang Geno Shi (Harvard Medical School, Boston, MA, USA) knew that high levels of glucose could inhibit the conversion of DNA methylation (5mC) to hydroxymethylation (5hmC) by the ten-eleven translocation (TET) dioxygenase family of proteins by influencing α-ketoglutarate levels (See Carey et al. and Xu et al.). Under their hypothesis, high blood glucose levels would increase 5hmC levels due to elevated TET activity, which in turn would deregulate gene expression; however, when Wu and colleagues analyzed global 5hmC levels in blood-derived genomic DNA, they actually discovered a decrease in 5hmC levels in diabetic patients when compared to healthy donors.
To reveal the whole story, the talented team focused the rest of their analyses on TET2, given previously described links between low TET2 expression and loss of 5hmC and cancer (Ko et al. and Lian et al.), which together establish TET2 as a novel tumor suppressor. Here is what they discovered:
- Analysis of normal glucose conditions in a human melanoma cell line overexpressing wild-type TET2, which display “normalized” 5hmC levels, revealed that the AMP-activated kinase (AMPK), a sensitive glucose sensor, phosphorylates and stabilizes TET2 (as evidenced by liquid chromatography with tandem mass spectrometry), which then promotes hydroxymethylation and tumor suppressive function
- Cell culture in high glucose levels characteristic of diabetes inhibits TET2 phosphorylation by AMPK, leading to protease-mediated degradation of TET2, a subsequent reduction 5hmC levels, and the appearance of tumorigenesis-associated characteristics, such as increased cell proliferation and anchorage-independent growth
- Further comparisons between healthy and high glucose culture conditions by hydroxymethylated DNA immunoprecipitation coupled with deep sequencing (hMeDIP-seq) indicates that 80% of the ~30,000 differentially hydroxymethylated regions encountered display decreases in 5hmC levels in high glucose conditions, with affects genes enriched for cancer and cancer-related pathways
- These changes led to the altered expression of 585 genes (both up- and down-regulated), with many associated with cell cycle regulation and various types of cancers
- However, exposure of high glucose cultured cells to the anti-diabetic, pro-longevity, and possible anti-cancer agent metformin reverses above-noted diabetes- and cancer-associated pathologies by promoting the AMPK-mediated phosphorylation of TET2 in vitro and in vivo in BALB/c nude mice xenografts
Sweet success!? The authors of this fascinating report anticipate that their description of how diabetes-associated high blood sugar levels promote the onset of tumorigenesis via deregulation of DNA hydroxymethylation will provide a means to treat and even prevent the onset of diabetes-associated cancer.