Functional interplay between E2F1 and chemotherapeutic drugs defines immediate E2F1 target genes crucial for cancer cell death.
The E2F1 transcription factor enhances apoptosis by DNA damage in tumors lacking p53. To elucidate the mechanism of a potential cooperation between E2F1 and chemotherapy, whole-genome microarrays of chemoresistant tumor cell lines were performed focusing on the identification of cooperation response genes (CRG). This gene class is defined by a synergistic expression response upon endogenous E2F1 activation and drug treatment. Cluster analysis revealed an expression pattern of CRGs similar to E2F1 mono-therapy, suggesting that chemotherapeutics enhance E2F1-dependent gene expression at the transcriptional level. Using this approach as a tool to explore E2F1-driven gene expression in response to anticancer drugs, we identified novel apoptosis genes such as the tumor suppressor TIEG1/KLF10 as direct E2F1 targets. We show that TIEG1/KLF10 is transcriptionally activated by E2F1 and crucial for E2F1-mediated chemosensitization of cancer cells. Our results provide a broader picture of E2F1-regulated genes in conjunction with cytotoxic treatment that allows the design of more rational therapeutics.
Engelmann
David
D
Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, Germany.
Knoll
Susanne
S
Ewerth
Daniel
D
Steder
Marc
M
Stoll
Anja
A
Pützer
Brigitte M
BM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D016000:Cluster Analysis; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors