DNA methylation at the 5 position of cytosine (5mC) is a critical epigenetic modification and plays key roles in various biological and pathological processes. The ten-eleven translocation (TET) families of dioxygenases primarily catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Several recent studies demonstrated that TET activities and the resultant 5hmC levels function as an epigenetic barrier for maintaining ES cell pluriopotency, governing organ development and preventing cancer progression. In particular, cancer cells have been shown to become more aggressive when TET gene expression or activity is compromised. These studies suggest that 5hmC and TET family proteins function as a checkpoint for cancer cell growth. For these reasons, investigating how TET proteins and 5hmC levels are regulated is necessary to fully understand how TET and 5hmC contribute to normal and pathological homeostasis. Based on solid preliminary data and the well-established deregulation of glucose uptake in cancer cells, we hypothesize that TET2 function is post-translationally regulated by distinctive post-translational modification (PTM), which can be modulated by glucose signaling. We further propose that the loss of the 5hmC tumor suppressor pathway in cancer cells is in part attributed to elevated glucose uptake and deregulated glucose signaling. The primary goal of this study is to understand how TET2 levels and activity are regulated by distinctive PTMs, which in turn impact on the TET2-controled DNA methylome/hydroxymethylome. Moreover, this proposal will unravel how protein-modifying enzymes differentially regulate TET2 PTMs in response to changes of glucose signaling. Specifically, in aim1 we will identify the cancer promoting changes to the hydorxymethylome/methylome that result from the deregulation of TET2 in response to aberrant glucose signaling, using the high resolution genome-wide mapping technologies we have developed.
In aim 2 &3, we will identify and characterize two types of glucose dependent PTMs observed on TET2, (glycosylation and phosphorylation), which are carried out by OGT and AMPK. Altogether, this proposal will characterize a novel regulatory circuit that maintains 5hmC levels through the posttranslational modifications of TET2 in response to glucose signaling. If successful, this proposal will significantly advance our understanding of the molecular mechanisms that facilitate cancer related changes at the epigenetic level in response to metabolic deregulation. This study will also establish a firm mechanistic link between changes in metabolic input to the adaption of the cancer epigenome. More importantly, identifying the molecular switch controlled by environmental cues that can turn on/off the 5hmC anti-tumor growth barrier in cancer will provide new therapeutic drug targeting strategies and treatments.
Aberrant glucose signaling and epigenetic deregulation, two common cancer hallmarks, have been extensively reported in most cancers. By unraveling the effect glucose signaling has on anti-cancer epigenetic hallmarks such as 5hmC and the tumor suppressor function of TET2, this proposal will ultimately provide a link between increased glucose uptake and the loss of 5hmC phenotypes and identify mechanisms to restore the 5hmC landscape to diseased cells. Thus, the outcome of this study will have significant impact on improvement of human health and the treatment of deadly diseases such as cancer.