Abstract B48: Epigenetic reprogramming of mitochondrial and metabolic functions plays a key role in arginine-deprivation based cancer therapy

Arginine deprivation has recently emerged as a promising cancer therapy, targeting tumor metabolism. This is due to the selective silencing of argininosuccinate synthetase 1 (ASS1) gene in many cancer types, rendering them “addicted” to external arginine. PEGylated arginine deiminase (ADI-PEG20), which effectively metabolizes arginine into citrulline and ammonia, has shown promising results in clinical trials for treating a variety of cancers. We have previously shown that ADI-PEG20 induces a novel type of tumor cell killing involving mitochondria dysfunction and chromatin autophagy, and that lysine demethylase KDM8 which regulates PKM2 plays an important role in tumor metabolism. We also observed in ADI-treated cells, the severe depletion of metabolites involved in glycolysis and glutaminolysis including alpha-ketoglutarate, a key cofactor for many of the KDMs. In parallel, many of the metabolic genes and nuclear genes involved in TCA cycles are coordinately down-modulated, which can be rescued by the addition of arginine. To study whether the coordinated gene repression is via epigenetic mechanism or due to the inhibition of KDMs, we analyzed the methylation status of histones at the promoter sites of metabolic genes, and found consistent accumulation of histone marks associated with transcriptional repression in ADI-PEG20-treated cells. Our results thus suggest that epigenetic reprogramming plays an important a role in the coordinated repression of metabolic gene expression in arginine-deprived cells. Citation Format: Hung-Jung Wang, Yen-Ling Yu, Sheng-Chieh Hsu, Cheng-Chin Kuo, Wen-Ching Wang, Chin-Pin Shuu, Hsing-Jien Kung. Epigenetic reprogramming of mitochondrial and metabolic functions plays a key role in arginine-deprivation based cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B48.