ASS1 as a Novel Tumor Suppressor Gene in Myxofibrosarcomas: Aberrant Loss via Epigenetic DNA Methylation Confers Aggressive Phenotypes, Negative Prognostic Impact, and Therapeutic Relevance

摘要: Purpose: The principal goals were to identify and validate targetable metabolic drivers relevant myxofibrosarcoma pathogenesis using a published transcriptome. Experimental Design: As the most significantly downregulated gene regulating amino acid metabolism, argininosuccinate synthetase ( ASS1) was selected for further analysis by methylation-specific PCR, pyrosequencing, immunohistochemistry of samples. roles ASS1 in tumorigenesis therapeutic relevance arginine-depriving agent pegylated arginine deiminase (ADI-PEG20) elucidated ASS1-deficient cell lines xenografts with without stable reexpression. Results: promoter hypermethylation detected samples strongly linked protein deficiency. latter correlated increased tumor grade stage independently predicted worse survival. auxotrophic susceptible ADI-PEG20 treatment, dose-dependent reductions viability growth attributable cell-cycle arrest S-phase. expression restored 2 3 5-aza-2′-deoxycytidine, abrogating inhibitory effect ADI-PEG20. Conditioned media following reexpression attenuated HUVEC tube-forming capability, which associated suppression MMP-9 an antiangiogenic corresponding xenografts. In addition delayed wound closure fewer invading cells Matrigel assay, reduced proliferation, induced G 1 -phase arrest, cyclin E inhibition soft agar xenograft assays. Conclusions: Our findings highlight as novel suppressor myxofibrosarcomas, loss methylation, clinical aggressiveness, sensitivity Clin Cancer Res; 19(11); 2861–72. ©2013 AACR .