Research Papers:

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

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

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Oncotarget. 2016; 7:82658-82670. https://doi.org/10.18632/oncotarget.12308

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Yan Long1,*, Wen-Bin Tsai1,*, Jeffrey T. Chang2, Marcos Estecio3, Medhi Wangpaichitr4, Naramol Savaraj4, Lynn G. Feun4, Helen H.W. Chen5, Macus Tien Kuo1

1Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, USA

3Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA

5Department 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: [email protected]

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


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.

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