Abstract 755: FK506 binding protein 51 (FKBP51) binds to p300 and acts as transcriptional co-regulator of ABCG2 gene expression in melanoma.

Abstract

Abstract Several lines of evidence support a role for FKBPs in chromatin modifications and cancer. Particularly for some of them, DNA association and regulation of gene expression has been demonstrated, mediated by histone- or transcription factor- chaperone activity. FKBP51 is an immunophilin that functions also as co chaperone of several proteins and receptors. We previously found this molecule has an essential role in melanoma resistance to the therapy and aggressiveness. Melanoma cells expressing stem cell markers (MCSC) produced high levels of FKBP51. In addition, the number of MCSC (identified by ABCG2 expression) was increased in FKBP51 over expressing melanoma cell lines. By converse, reduced expression of cancer stemness genes was measured in FKBP51 silenced melanoma. Since ABCG2+ cells also contained high levels of the general transcriptional co-activator, namely E1A binding protein p300, we hypotesized that FKBP51 might act as a p300 co chaperone with a role in transcriptional regulation of stemness markers. By co-IP assays, we show that FKBP51 interacts with p300 and partecipates in transcriptional complexes with Smad 2 and p300. By chromatin immunoprecipitation assays (ChIP) we demonstrate that FKBP51 binds to chromatin. We used different couples of primers to amplify different regions of the ABCG2 promoter, in FKBP51-immunoprecipitated chromatin and found enrichment of DNA fragments corresponding to a first sequence localized at 3450 bp (-3450) from the transcription start site (TSS), a second at -3219, and a third at -939. Differently, no enrichment in closest regions was found, suggesting the specificity of FKBP51 binding to ABCG2 promoter. In addition, we found p300 bound to the same regions of ABCG2 promoter, and such binding was impaired by FKBP51 downmodulation, suggesting the immunophilin regulatated the binding of p300 to DNA. In conclusion, our study supports the conclusion that FKBP51 partecipates in the transcriptional apparatus that controls expression of melanoma stemness genes, acting as co chaperone of p300. Citation Format: Simona Romano, Giovanna Nappo, Elena Cesaro, Antonio Candela, Maria Fiammetta Romano. FK506 binding protein 51 (FKBP51) binds to p300 and acts as transcriptional co-regulator of ABCG2 gene expression in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 755. doi:10.1158/1538-7445.AM2013-755