Arginine deprivation induces mitochondria dysfunction through epigenetic gene silencing of respiratory chain genes
Sheng-Chieh Hsu1, 2, 3, Yen-Ling Yu4, Hung-Jung Wang3*, Hsing-Jien Kung4, 5*
1Graduate Program of Biotechnology in Medicine, NTHU & NHRI
2Department of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan
3Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan
4Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
5Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan
Argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme of urea cycle, is often downregulated in several cancers including breast, prostate, liver, lymphoma and melanoma. Since ASS1 is also responsible for de novo synthesis of intracellular arginine, loss of ASS1 expression renders cancer cells auxotrophic for arginine; therefore, arginine deprivation becomes a promising method for cancer therapy. Currently, an arginine deiminase derived from mycoplasma, ADI-PEG20 has been pushed through phase III clinical trial. By depleting circulating arginine, it can starve cancer cells to death while sparing normal cells. Despite all these success in cancer therapy, the mechanisms behind the arginine deprivation-induced growth inhibition in ASS1-deficient cancers remains poorly understood. Recently, we discovered that arginine deprivation increased inhibitory methylation of H3K9 and H3K27 and silenced gene expressions of mitochondrial respiratory chain. Examining the H3K9 and K27 methylation status on these genes' promoters, we found that the promoter regions were highly methylated, suggesting that these genes were epigenetically silenced by arginine depletion. Arginine deprivation decreases intracellular α-ketoglutarate, which is a cofactor for histone demethylases, indicating arginine deprivation induces a landscape changes of histone methylation through downmodulating of histone demethylases. Downregulation of respiratory chain genes by arginine deprivation also impaired mitochondrial functions and caused abnormal mitochondrial fusion/fission, which lead to activation of AMPK and downregulation of mTOR pathway. Furthermore, arginine deprivation also decreased TAZ protein both in cytosol and nucleus, suggesting arginine deprivation may exert its anti-proliferation property through inhibiting Hippo signaling pathway.