The transcription factor FLI1 promotes cancer progression by modulating the hTERT/CCND1/E2F axis of cell cycle regulation

ABSTRACT: The non-coding genome contributes substantially to the total cellular DNA mass and is thoutht to host regulatory cis-acting element, but may also code for some regulatory transcripts. Despite ist contribution to the genomic mass, it has barely recieved scientific attention. Much emphasis has been laid on the approximaetly 2% coding Region, although its transcription, in most cases is regulated at the level of the non-coding genome. In recent years, several studies have revealed disease-associated somatic mutations in regulatory regions of the non-coding genome. One most prominent example is the hotspot mutations in the core promoter region of the TERT gene. In several cancer entities, these alterations have been associated with dysregulation of telomerase activity and tumorigenesis. Novel binding sites are created for transcription factors of the ETS family and GABP for example has been shown to bind to these novel ETS sites. The entire spectrum of ETS family members that can bind is however still lacking. In ordert o fill this knowledge gap and understand the impact of such binding on tumor biology, we have used functional protein microarrays to identify ETS members that preferentially bind the mutant promoter and by means of transcription profiling, we have identified downstream targets of the binding events. We have used siRNA to knockdown FLI-1 and hTERT in cell lines from three cancer entities (NSCLC, PDAC and MCC) with the help oft he illumina beadchip arrays and we compared the transcriptional profiles of the cell lines under different knockdown conditions. We Identify CCND1 and E2F2 as direct targets of both TERT and FLI-1, and CMTM7 as an FLI1-only target. We show, for different cancer entities, that FLI-1 binds the TERT promoter and accelerates progression through the cell cycle by enhancing E2F2 and CCND1 expression

ORGANISM(S): Homo sapiens

SUBMITTER: Smiths Lueong 

PROVIDER: E-MTAB-7452 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress