title: Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer.
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.
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Thurlings
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: L M
authors.initials: LM
authors.lastname: Martínez-López
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Westendorp
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Zijp
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Kuiper
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Tooten
authors.affiliation: Department of Molecular Virology, Immunology, Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Kent
authors.affiliation: Department of Molecular Virology, Immunology, Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Vos
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Burgering
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Bruin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004249:DNA Damage; D050702:E2F7 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D050702:E2F7 Transcription Factor; C481054:E2F7 protein, human; C504723:E2F8 protein, human; C504722:E2F8 protein, mouse; C479901:E2f7 protein, mouse; D012097:Repressor Proteins