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 W. Chen, Macus Tien Kuo

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8 Citations (Scopus)

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-azadeoxycytidine (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.

Original languageEnglish
Pages (from-to)82658-82670
Number of pages13
JournalOncotarget
Volume7
Issue number50
DOIs
Publication statusPublished - 2016 Jan 1

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Argininosuccinate Synthase
DNA Methylation
Starvation
Cisplatin
Arginine
Therapeutics
Up-Regulation
decitabine
Synthetic Lethal Mutations
Down-Regulation
Epigenomics

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Long, Yan ; Tsai, Wen Bin ; Chang, Jeffrey T. ; Estecio, Marcos ; Wangpaichitr, Medhi ; Savaraj, Naramol ; Feun, Lynn G. ; Chen, Helen W. ; Kuo, Macus Tien. / 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. In: Oncotarget. 2016 ; Vol. 7, No. 50. pp. 82658-82670.
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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-azadeoxycytidine (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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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. / Long, Yan; Tsai, Wen Bin; Chang, Jeffrey T.; Estecio, Marcos; Wangpaichitr, Medhi; Savaraj, Naramol; Feun, Lynn G.; Chen, Helen W.; Kuo, Macus Tien.

In: Oncotarget, Vol. 7, No. 50, 01.01.2016, p. 82658-82670.

Research output: Contribution to journalArticle

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AU - Long, Yan

AU - Tsai, Wen Bin

AU - Chang, Jeffrey T.

AU - Estecio, Marcos

AU - Wangpaichitr, Medhi

AU - Savaraj, Naramol

AU - Feun, Lynn G.

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AU - Kuo, Macus Tien

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