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.

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.

• Authors: Yan Long, Wen-Bin Tsai, Jeffrey T Chang, Marcos Estecio, Medhi Wangpaichitr, Naramol Savaraj, Lynn G Feun, Helen H W Chen, Macus Tien Kuo
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 50 Pg. 82658-82670 (Dec 13 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27765932 (Publication Type: Journal Article)

Chemical References

• BHLHE40 protein, human
• Basic Helix-Loop-Helix Transcription Factors
• HIF1A protein, human
• Histone Deacetylase Inhibitors
• Homeodomain Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• MYC protein, human
• Proteasome Inhibitors
• Proto-Oncogene Proteins c-myc
• Polyethylene Glycols
• Arginine
• Hydrolases
• ADI PEG20
• Argininosuccinate Synthase
• Cisplatin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Arginine (deficiency)
• Argininosuccinate Synthase (genetics, metabolism)
• Basic Helix-Loop-Helix Transcription Factors (genetics, 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, metabolism)
• Humans
• Hydrolases (pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Neoplasms (drug therapy, enzymology, genetics, pathology)
• Polyethylene Glycols (pharmacology)
• Promoter Regions, Genetic
• Proteasome Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Interference
• Signal Transduction (drug effects)
• Time Factors
• Transcription, Genetic (drug effects)
• Transfection