The Role of Histidine in Tumor Metabolism and Epigenetic Regulation

Tumor microenvironment provides growth signals and regulates the metabolism of tumor cells, which is critical for tumor progression. One of most abundant amino acid in the serum, glutamine, supports cell proliferation and TCA cycle intermediate metabolites by regulating purine/pyrimidine synthesis and anaplerotic reactions, respectively. During tumor growth, over consumption of glutamine causes regional glutamine deficiency in tumor cell mass, however, it is unclear how cancer cells cope with glutamine deprivation. Recently, we demonstrated that CTP synthase filament formation could be a strategy for cancer cell survival under glutamine deprivation (W.C. Lin et al., Sep, 2018, CELL REPORTS). Histidine, an essential amino acid, is a major player to induce CTP synthase filament formation through methylation under glutamine deprivation. Histidine donates one carbon units coupled with folate metabolism for the re-methylation of homocysteine (methionine synthesis), suggesting that histidine could regulate methylation. Therefore, we hypothesize that histidine may play a role on the regulation of cancer cell metabolism through methylation. According the present works, we propose that filaments formation might be the general mechanism to serve as the reservoir for proteins preservation under the adverse environments. We will further investigate what molecules work cooperatively to assemble this filament structure by APEX proximity labeling assay. Additionally, we will dissect molecular mechanisms to understand the role of histidine on methylation. We plan to utilize interdisciplinary approach to assess the impact of histidine on metabolism and epigenetic regulation. These works will set out details on how cells achieved favorable position against adverse environment by changing their metabolism status and gene expression profile. The result of the study can provide new strategies and opportunities in treating cancers.

Project ID:PC10901-1928
External Project ID:MOST108-2321-B182-004-MY3