Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1α, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation

• Published in: Oncotarget Vol. 7; no. 50; pp. 82658 - 82670
• Main Authors: Long, Yan, Tsai, Wen-Bin, Chang, Jeffrey T, Estecio, Marcos, Wangpaichitr, Medhi, Savaraj, Naramol, Feun, Lynn G, Chen, Helen H W, Kuo, Macus Tien
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 13.12.2016
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Arginine - deficiency; Argininosuccinate Synthase - genetics; Argininosuccinate Synthase - metabolism; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cisplatin - pharmacology; DNA Methylation - drug effects; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors - pharmacology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Hydrolases - pharmacology; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Polyethylene Glycols - pharmacology; Promoter Regions, Genetic; Proteasome Inhibitors - pharmacology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Research Paper; RNA Interference; Signal Transduction - drug effects; Time Factors; Transcription, Genetic - drug effects; Transfection; arginine-starvation; DNA methylation; cisplatin; DEC1-HIF-1α-c-Myc axis; ASS1
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12308

Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression. Moreover, it was reported that cisplatin suppresses ASS1 expression through ASS1 promoter methylation, leading to synthetic lethality to ADI-PEG20 treatment. We report here that cisplatin supppresses ASS1 expression is due to upregulation of HIF-1α and downregulation of c-Myc, which function as negative and positive regulators of ASS1 expression, respectively, by reciprocal bindings to the ASS1 promoter. In contrast, we found that Aza-dC induces ASS1 expression by downregulation of HIF-1α but upregulation of c-Myc. We further demonstrated that the clock protein DEC1 is the master regulator of HIF-1α and c-Myc that regulate ASS1. cDDP upregulates DEC1, whereas Aza-dC suppresses its expression. Using two proteasomal inhibitors bortezomib and carfilzomib which induce HIF-1α accumulation, we further demonstrated that HIF-1α is involved in ASS1 silencing for the maintenance of Arg auxotrophy for targeted Arg-starvation therapy.