title: 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.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tsai
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Marcos
authors.initials: M
authors.lastname: Estecio
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
authors.forename: Medhi
authors.initials: M
authors.lastname: Wangpaichitr
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
authors.forename: Naramol
authors.initials: N
authors.lastname: Savaraj
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Feun
authors.affiliation: Department of Radiation Oncology, National Cheng Kung University, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.
authors.forename: Helen H W
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001120:Arginine / Q000172:deficiency*; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D061988:Proteasome Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
chemical_list: D001120:Arginine; D001124:Argininosuccinate Synthase; D051792:Basic Helix-Loop-Helix Proteins; D002945:Cisplatin; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D006867:Hydrolases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011092:Polyethylene Glycols; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C107989:BHLHE40 protein, human; C497442:HIF1A protein, human; C489427:MYC protein, human; C512527:ADI PEG20
keywords: ASS1; DEC1-HIF-1α-c-Myc axis; DNA methylation; arginine-starvation; cisplatin