There is unequivocal data implicating the E2F family of transcription factors as key regulators of proliferation, differentiation and neoplasia. In addition, we recently showed that the ratio between activating E2Fs (eg: E2F1) and inhibitory E2Fs (eg: E2F7) may regulate apoptotic responses (1,2). We now present the results of our recent studies that identify an important, unique and non-redundant role for E2F7 in suppressing sensitivity to cytotoxic stimuli. Dysregulation of responses to UV or chemotherapy-induced cytotoxicity are fundamental to the development of squamous cell carcinoma (SCC) and its resistance to chemotherapeutics. Thus, identification of the downstream effectors that regulate E2F7-dependent sensitivity to the major causative factor in skin carcinogenesis (UV) or sensitivity to the major chemotherapeutic agents will be of significant clinical and biological interest.
Using a series of knockout and overexpression strategies we show that E2F7 antagonises E2F1-dependent apoptosis in response to UV and doxorubicin in keratinocytes and SCC cell lines. This is likely to have clinical implications since E2F7 is overexpressed in human SCC approximately 200 fold. We go on to show that cytotoxic-sensitive SCC cell lines have a low E2F7/E2F1 ratio and insensitive SCC cell lines have a high E2F7/E2F1 ratio. Using these sensitive and insensitive cell lines, coupled with E2F7 knockdown strategies, we conducted an -omics based screen and identified 4 genes that may act as downstream effectors of E2F1/7 mediated cytotoxic sensitivity.