ピルビン酸脱水素酵素PDHによるヒストンアセチル化を介した遺伝子発現制御機構の解析

抄録

When organisms are exposed to hypoxic condition, physiological processes such as metabolism, respiration, and erythropoiesis are adjusted for adaptation. Hypoxia-Inducible Factor (HIF) is a key transcription factor which is involved in these processes. Hypoxic tumor microenvironment alters the character of cancer cells and induces malignant phenotypes. Pyruvate dehydrogenase (PDH) catalyzes the production of acetyl CoA from pyruvate, thus connecting glycolysis and the TCA cycle. PDH functions as a complex consisting of five major subunits; E1α, E1β, E2, E3 and E3BP. HIF induces PDH kinase and promotes the phosphorylation of PDH-E1α to inhibit its activity under hypoxic condition. This pathway leads to the energetic conversion under hypoxia: from oxidative phosphorylation to glycolysis.

In addition to the metabolic function in mitochondria, nuclear localization of PDH was found in breast cancer cell lines. When these cells were cultured under hypoxic condition, phosphorylation of PDH-E1α and downregulation of PDH-E1β occurred. Knockdown (KD) of PDH decreased histone H3 acetylation, which was also found upon hypoxic treatment. Finally, numbers of gene were found to be up- or down-regulated in PDH-KD breast cancer cells. Upregulated genes were categorized into gene groups, such as apoptosis, inflammation, or oxygen response, which is linked to the malignancy of cancer cells. These results indicate that tumor progression could be suppressed by maintaining PDH activity in the nucleus. I would like to discuss a possible pharmacological approach to regulate the nuclear PDH.