E2f8 mediates tumor suppression in postnatal liver development

Kent, Lindsey N.; Rakijas, Jessica; Pandit, Shusil K.; Westendorp, Bart; Chen, Hui Zi; Huntington, Justin T.; Tang, Xing; Bae, Sooin; Srivastava, Arunima; Senapati, Shantibhusan; Koivisto, Christopher S.; Martin, Chelsea K.; Cuitiño, Maria C.; Perez, Miguel; Clouse, Julian M.; Chokshi, Veda; Shinde, Neelam; Kladney, Raleigh D.; Sun, Dongqing; Perez-Castro, Antonio J.; Matondo, A.B.; Nantasanti, Sathidpak; Mokrý, Michal; Huang, Kun; Machiraju, Raghu; Fernández, Soledad; Rosol, Thomas J.; Coppola, Vincenzo; Pohar, Kamal S.; Pipas, James M.; Schmidt, Carl; Bruin, Alain de; Leone, Gustavo

doi:10.1172/jci85506

Cited by 83 publications

(110 citation statements)

References 40 publications

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“…LKO livers developed numerous tumors of various sizes, whereas control mice were relatively tumor free. These results are consistent with a report by Kent et al, where LKO mice spontaneously developed liver tumors during aging and developed more tumors than controls in the DEN tumor induction model . A number of mechanisms could explain the sensitivity of LKO mice to liver tumorigenesis.…”

Section: Discussionsupporting

confidence: 93%

The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice

et al. 2019

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The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well characterized; however, it is unclear whether diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid‐only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (liver‐specific E2f7/E2f8 knockout; LKO) were recently reported to have a polyploidization defect, but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20‐fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function, but became highly tumorigenic when challenged with tumor‐promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out‐compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild‐type (WT) mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. WT diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration (LR). Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Conclusion: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.

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Section: Discussionsupporting

confidence: 93%

The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice

et al. 2019

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“…Moreover, cyclin F targets the ribonucleotide reductase RRM2 and stem loop binding protein SLBP for proteasomal degradation, which provides a balanced dNTP pool for DNA repair, and prevents SLBP-dependent accumulation of H2AFX mRNA translation to reduce susceptibility to genotoxic stress (D'Angiolella et al, 2012;Dankert et al, 2016). Interestingly, both SLBP and RRM2 are bona fide targets of E2F7/8 (Westendorp et al, 2012;Kent et al, 2016). Interestingly, in response to irradiation, cyclin F has been shown to be downregulated in an ATR-dependent manner, which resulted in stabilization of SLBP and RRM2 to promote DNA repair (D'Angiolella et al, 2012;Dankert et al, 2016).…”

Section: Of 14mentioning

confidence: 99%

“…In addition to RRM2 and SLBP, cyclin F targets CDC6 for degradation, which is also transcriptionally regulated by atypical E2Fs (Westendorp et al, 2012;Kent et al, 2016). Thus, E2F-dependent transcription and SCF cyclin F appear to have partially overlapping functions.…”

Section: Of 14mentioning

confidence: 99%

“…Our previous studies have revealed that classical E2F7/8 target genes, such as CDT1, CDC6, and RAD51, are involved in DNA replication, repair, and metabolism (Westendorp et al, 2012;Kent et al, 2016). Our previous studies have revealed that classical E2F7/8 target genes, such as CDT1, CDC6, and RAD51, are involved in DNA replication, repair, and metabolism (Westendorp et al, 2012;Kent et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

et al. 2019

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E2F7 and E2F8 act as tumor suppressors via transcriptional repression of genes involved in S‐phase entry and progression. Previously, we demonstrated that these atypical E2Fs are degraded by APC/CCdh1 during G1 phase of the cell cycle. However, the mechanism driving the downregulation of atypical E2Fs during G2 phase is unknown. Here, we show that E2F7 is targeted for degradation by the E3 ubiquitin ligase SCFcyclin F during G2. Cyclin F binds via its cyclin domain to a conserved C‐terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCFcyclin F remains stable during G2. Furthermore, SCFcyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCFcyclin F nor the CY motifs in the C‐terminus of E2F8, implying a different regulatory mechanism than for E2F7. Importantly, depletion of cyclin F causes an atypical‐E2F‐dependent delay of the G2/M transition, accompanied by reduced expression of E2F target genes involved in DNA repair. Live cell imaging of DNA damage revealed that cyclin F‐dependent regulation of atypical E2Fs is critical for efficient DNA repair and cell cycle progression.

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“…Under the in vivo stress of DMBA/TPA skin carcinogenesis model, inactivation of E2f7/8 gives rise to the acceleration of tumorigenesis and deteriorating progression 75. Temporal-specific ablation of E2f8 in the liver at 1-2 weeks of age resulted in severe liver cancer, but not in older age, suggesting that E2F8 acts as a tumor suppressor in postnatal liver development 27. These contradictory results might be due to studies performed in different cell lines and context.…”

Section: E2f8 and Diseasesmentioning

confidence: 99%

E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma

Xiao

Liu

et al. 2017

J. Cancer

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E2F transcriptional factors are widely expressed in a number of tissues and organs, possessing many regulatory functions related to cellular proliferation, differentiation, DNA repair, cell-cycle and cell apoptosis. E2F8 is a recently identified member of the E2F family with a duplicated DNA-binding domain feature discriminated from E2F1-6, controlling gene expression in a dimerization partner-independent manner. It is indispensable for angiogenesis, lymphangiogenesis and embryonic development. Although E2F8 and E2F7 perform complementary and overlapping functions in many cell metabolisms, E2F8, but not E2F7, overexpresses remarkably in hepatocellular carcinoma (HCC) to facilitate the HCC occurrence and development via activating a E2F1/ Cyclin D1 signaling pathway to regulate the G1- to S-phase transition of cell cycle progression or transcriptionally suppressing CDK1 to induce hepatocyte polyploidization. It also involves closely a variety of cellular physiological functions and pathological processes, which may bring a new breakthrough for the treatment of certain diseases, especially the HCC. Here, we summarize the latest progress of E2F8 on its relevant functions and mechanisms as well as potential application.

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E2f8 mediates tumor suppression in postnatal liver development

Cited by 83 publications

References 40 publications

The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice

The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma

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