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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

2016; Impact Journals LLC; Volume: 7; Issue: 50 Linguagem: Inglês

10.18632/oncotarget.12308

1949-2553

Yan Long, Wen-Bin Tsai, Jeffrey T. Chang, Marcos R. Estecio, Medhi Wangpaichitr, Naramol Savaraj, Lynn G. Feun, Helen H.W. Chen, Macus Tien Kuo,

Polyamine Metabolism and Applications

// Yan Long 1, * , Wen-Bin Tsai 1, * , Jeffrey T. Chang 2 , Marcos Estecio 3 , Medhi Wangpaichitr 4 , Naramol Savaraj 4 , Lynn G. Feun 4 , Helen H.W. Chen 5 , Macus Tien Kuo 1 1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, USA 3 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA 5 Department of Radiation Oncology, National Cheng Kung University, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan * These authors have contributed equally to this work Correspondence to: Macus Tien Kuo, email: tkuo@mdanderson.org Keywords: cisplatin, arginine-starvation, DEC1-HIF-1α-c-Myc axis, ASS1, DNA methylation Received: March 19, 2016 Accepted: September 19, 2016 Published: September 28, 2016 ABSTRACT 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.