1. Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer
- Author
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Thurlings, I, Martínez-López, L M, Westendorp, B, Zijp, M, Kuiper, R, Tooten, P, Kent, L N, Leone, G, Vos, H J, Burgering, B, de Bruin, A, LS Pathobiologie, Dep Gezondheidszorg Landbouwhuisdieren, dPB RMSC, LS Pathobiologie, Dep Gezondheidszorg Landbouwhuisdieren, and dPB RMSC
- Subjects
Keratinocytes ,0301 basic medicine ,Cancer Research ,Skin Neoplasms ,GENES ,DNA damage ,DNA-BINDING DOMAINS ,Apoptosis ,PROGRESSION ,Biology ,medicine.disease_cause ,CELL-PROLIFERATION ,Mice ,03 medical and health sciences ,0302 clinical medicine ,E2F7 Transcription Factor ,Genetics ,medicine ,Animals ,Humans ,E2F1 ,TRANSCRIPTION ,E2F ,Molecular Biology ,ATYPICAL E2FS ,Mice, Knockout ,DAMAGE ,CARCINOGENESIS ,Cell cycle ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,medicine.anatomical_structure ,TARGET ,030220 oncology & carcinogenesis ,FAMILY-MEMBER ,Immunology ,Cancer research ,Original Article ,Skin cancer ,biological phenomena, cell phenomena, and immunity ,Keratinocyte ,Carcinogenesis ,E2F Transcription Factors ,DNA Damage - Abstract
E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8-deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target genes that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress.
- Published
- 2017