An emerging hallmark of cancer is that malignant cells modulate metabolic pathways to promote cancer progression. Although a series of reports have demonstrated that the synthetic pathway of the non-essential amino acid serine is upregulated in cancer, it remains poorly understood that how serine catabolism contributes to cancer progression. My preliminary studies demonstrated that the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) is overexpressed in many cancers via induction by a combination of hypoxia-inducible factors 1 (HIF-1) and Myc under hypoxia (low oxygen). Hypoxia is a common microenvironmental stress in solid tumor. Given that hypoxia contributes to tumor aggressiveness and resistance to cancer therapy, it is pressing to determine the possible role(s) of SHMT2 induction in tumor adaption to hypoxia. SHMT2 converts serine to glycine, with concurrent generation of one-carbon unit donor methylene-THF. I found that knockdown of SHMT2 enhanced cellular reactive oxygen species (ROS) level under hypoxia, indicating a novel role of SHMT2 in maintaining cellular redox balance upon hypoxic stress. In addition, repression of SHMT2 abolished DNA/histone hypermethylation stimulated by hypoxia, suggesting that one-carbon unit flux from SHMT2 may be critical for cellular methyltransferase activity, which contributes to epigenetic modification of chromosomes. Since Myc is required for the basal expression and hypoxic induction of SHMT2, it is critical to define the role of SHMT2-dependent DNA/histone hypermethylation in myc- dependent tumorigenesis. This enhanced methylation may correlate with the inability of neuroblastoma cells to activate lineage-specific genes involved in cellular differentiation. To address these issues, two Specific Aims are proposed: 1) Identify how hypoxia-induced SHMT2 regulates mitochondrial redox balance. 2) Define the role(s) of histone/DNA methylation regulated by SHMT2 under hypoxia. Through these proposed studies I hope to broaden the understanding of the metabolic regulation of redox control and epigenetic modification under hypoxia, and develop new therapeutic approaches targeting hypoxic cancer.
The discovery of the altered serine metabolic pathway that contributes to tumor malignancy opens up new therapeutic approaches to the treatment of these tumors. The experiments I proposed here will elucidate the role of hypoxia-induced serine hydroxymethyltransferase 2 in regulating cellular redox and epigenetics, thus significantly contribute to our understanding of the connection between serine and one-carbon unit metabolism, providing new targets for cancer therapy.
