Since SS18 SSX itself lacks direct DNA binding domains or activity, it has been

Congruent with this, romidepsin and SB939 induce a time dependent increase in the expression of both Egr1 and Atf3, in accordance プロテイン 阻害剤 with a significant decrease in H3K27me3 levels on their promoter regions. Taken together, these findings suggest that HDAC inhibitors derepress SS18 SSX target genes, at least in part through disrupting the recruitment of TLE1 and its associated HDAC/PcG proteins to the SS18 SSX complex, thus leading to loss of the repressive H3K27me3 mark and restored gene expression. DISCUSSION The nature through which SS18 SSX dysregulates transcription is a long standing question in the synovial sarcoma field. Previous studies have shown that SS18 SSX can interact with components of the TrxG transcriptional activator complexes, as well it has been found to co localize with PcG repressor factors.<br><br> Although these observations suggest a potential role for chromatin remodeling in SS18 SSX mediated Lenalidomide 構造 gene silencing, it remained unclear how SS18 SSX controls the TrxG PcG balance and, more importantly, how this fusion oncoprotein regulates gene expression in the absence of any known DNA binding domain. In this study, we identify a core SS18 SSX transcriptional complex that is required for epigenetic silencing of tumor suppressor genes in synovial sarcoma. For assembly of this complex, the SS18 SSX fusion oncoprotein serves as a scaffolding protein to connect together two important transcriptional regulators, ATF2 and TLE1. SS18 SSX alone cannot bind to DNA, and its recruitment to target promoters is dependent on the sequence specific transcriptional activator ATF2.<br><br> In this manner, SS18 SSX recruitment of a TLE1 containing repressor complex functions to silence buy LY2603618 ATF2 target genes. Modulation of ATF2 has also been identified in other cancers and interestingly, both activation and inhibition of ATF2 have been linked to tumorigenesis indicating that ATF2 function in cancer is context dependent. For instance, in melanoma, activation of ATF2 which is associated with predominantly nuclear localization appears to be important for tumorigenesis and metastasis, while suppression of ATF2 leads to increased susceptability to various cell stressors. Conversely, in other cancers, loss or decreased expression of ATF2 is associated with an increased incidence of tumorgenesis and metastasis.<br><br> Putative ATF2 inactivating mutations in lung cancer have been identified, and in melanoma increased ATF2 cytoplasmic localization is associated with reduced tumorgenic potential and a better prognosis. Atf2 heterozygous mice exhibit an increased incidence of breast cancer after a long latency period suggesting that an additional hit is required for tumor progression in this background. However, this second hit may in part involve loss of ATF2, as in all tumors examined ATF2 was undetectable. In a skin cancer model in mice, deletion of Atf2 was sufficient to increase the appearance of precancerous lesions. However, in this model loss of ATF2 appears to promote tumorgenesis and is unlikely involved in initation. Together, these studies support a fundamental role for ATF2 in tumorgenesis, and highlight the varied mechanisms employed to inactivate its function.