E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice
Open accessAbstract
Background and Aims: Up‐regulation of the E2F‐dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F‐dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking. Approach and Results: Here, we generated transgenic mice with doxycycline‐controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine‐induced liver tumors. Conclusion: Collectively, our findings demonstrate that atypical E2Fs can override cell‐cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.
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E2f7 and E2f8, as well as polyploidy, suppress tumorigenesis.
“E2f7 and E2f8, as well as polyploidy, are known to suppress tumorigenesis (43–46).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [46]
The Results section ('E2F7/8 Transgene Induction in Liver Tumors Causes Replication Stress and Inhibits Neoplastic Growth'; page unavailable) says E2f7 and E2f8 overexpression inhibits tumorigenesis in mouse liver tumors. Our copy does not say that polyploidy suppresses tumorigenesis; the References section only lists a study about E2F8's role in polyploidization. (LLM, conf=0.88)
Experimental — accuracy not yet measuredE2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis.
“while E2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis (Kent et al. 2016;Moreno et al. 2021;Wilkinson et al. 2019;Zhang et al. 2018).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Moreno et al. 2021
The Results section reports that E2f7 and E2f8 overexpression inhibited tumorigenesis in mouse liver cancers. Our copy does not establish the separate claim that polyploidy suppresses tumorigenesis; its reference to polyploidization concerns E2F8’s role in that process, not a tumor-suppressing effect. (LLM, conf=0.85)
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Cites
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“This indicates that transgene expression in tumor cells might be epigenetically silenced, which is a known phenomenon for tetracycline-inducible cytomegalovirus (CMV) promoters.(22-26) To further support this concept of E2F7/8mediated selection pressure, we then set out to mimic it in vitro.”
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“In further support of this notion, recent work showed that high levels of E2F-dependent transcription, through loss of E2F7, promote resistance of cancer cells toward poly(adenosine diphosphate-ribose) polymerase inhibitors and interstrand-crosslinking drugs such as cisplatin and mitomycin C.(32,33) In conclusion, the…”
BackgroundSynergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer
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“316 maintain a high level of E2F-dependent transcription for boosting DNA repair and restarting DNA replication.(20,31) As a consequence, the cell-cycle arrest seen in CHK1-depleted cells is rescued by additional loss of atypical E2Fs.”
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“In further support of this notion, recent work showed that high levels of E2F-dependent transcription, through loss of E2F7, promote resistance of cancer cells toward poly(adenosine diphosphate-ribose) polymerase inhibitors and interstrand-crosslinking drugs such as cisplatin and mitomycin C.(32,33) In conclusion, the…”
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E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma
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“(18,21) A second notion is that some in vitro studies using cancer cell lines suggested that overexpression of E2F8 promoted tumor cell proliferation.(15,16,17,30) However, we now demonstrate that E2F7/8 overexpression invokes a strong selection pressure on cells.”
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“This indicates that transgene expression in tumor cells might be epigenetically silenced, which is a known phenomenon for tetracycline-inducible cytomegalovirus (CMV) promoters.(22-26) To further support this concept of E2F7/8mediated selection pressure, we then set out to mimic it in vitro.”
BackgroundFeedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression
Boekhout, M., Yuan, R.-X., Wondergem, A. P., Segeren, H. A., Liere, E. A., Awol, N., Jansen, I., Wolthuis, R., de Bruin, A., & Westendorp, B. (2016) · EMBO Reports · doi:10.15252/embr.201540984 · Cited by 36 · cited 8× · see citing works
“We previously demonstrated strong inhibition of proliferation and induction of apoptosis for up to 4 days,(1,18) but now we induced E2F7 overexpression for up to 20 days.”
BackgroundInfluentialSelf-citationChk1 and 14‐3‐3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest
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“Because E2F7 and E2F8 repress multiple DNA repair genes, their overexpression would not only predispose cells to replication stress–induced double strand breaks but also inhibit the repair of such lesions.(1,20,21) Indeed, E2f7 and E2f8 Tg mice showed a marked increase of gamma H2A.”
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“(18,21) A second notion is that some in vitro studies using cancer cell lines suggested that overexpression of E2F8 promoted tumor cell proliferation.(15,16,17,30) However, we now demonstrate that E2F7/8 overexpression invokes a strong selection pressure on cells.”
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“This indicates that transgene expression in tumor cells might be epigenetically silenced, which is a known phenomenon for tetracycline-inducible cytomegalovirus (CMV) promoters.(22-26) To further support this concept of E2F7/8mediated selection pressure, we then set out to mimic it in vitro.”
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“This indicates that transgene expression in tumor cells might be epigenetically silenced, which is a known phenomenon for tetracycline-inducible cytomegalovirus (CMV) promoters.(22-26) To further support this concept of E2F7/8mediated selection pressure, we then set out to mimic it in vitro.”
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“E2F7 is a cellular context-dependent transcription factor that might act as a positive or negative regulator in different cancer types (22, 23).”
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“RPE cell lines harboring the Tet Repressor, FUCCI4 system, fluorescently tagged H2B, 53BP1 and HRAS were created using lentiviral transduction with the third-generation lentiviral packaging system as previously described [76].”
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“Discussion As important transcription factors, members of the E2F transcription factor protein family play a key role in regulating downstream gene transcription (13-17).”
BackgroundLiu, Y., Tang, H., Zhang, Y., Wang, Q., Li, S.-Y., Wang, Z.-Y., & Shi, X. (2023) · Human Cell · doi:10.1007/s13577-022-00854-7 · Cited by 13
“reported that E2F7 inhibited diethylnitrosamine-induced liver tumor growth in adult mice, implying that E2F7 might exert different effects in liver cancers with different etiologies [40].”
BackgroundMoreno, E., Pandit, S. K., Toussaint, M. J. M., Bongiovanni, L., Harkema, L., van Essen, S. C., van Liere, E. A., Westendorp, B., & de Bruin, A. (2021) · Cancers · doi:10.3390/cancers13092033 · Cited by 12 · see citing works
“Importantly, we showed previously that the main tumor suppressive mechanism of atypical E2Fs is their repressive function on E2Fdependent transcription [10,31].”
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The roles of E2F7 in cancer: Current knowledge and future prospects
Chen, K.-Q., Lei, H.-B., Liu, X., & Wang, S.-Z. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e34362 · Cited by 12 · see citing works
“In the process of oncogene-induced senescence, E2F7 inhibits a number of E2F target genes to enhance cell cycle arrest and prevent the oncogenic transformation by cooperating with retinoblastoma protein (RB) [8].”
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“E2F7 has been identified as a cancer-promoting gene in glioblastoma, liver cancer, and colon cancer [39–41].”
BackgroundZhang, C.-G., Cui, Y.-X., Wang, G.-N., Zhao, W.-G., Zhao, H., Huang, X.-S., Zhang, M., & Li, W.-C. (2021) · Journal of Healthcare Engineering · doi:10.1155/2021/5790416 · Cited by 8 · see citing works
RetractedWu, H., & Zheng, B. (2024) · Journal of biochemical and molecular toxicology · doi:10.1002/jbt.70015 · Cited by 6 · see citing works
Systematic decoding of functional enhancer connectomes and risk variants in human glioma
Bi, J., Mo, W., Liu, M., Song, Y., Xiao, Q., Fan, S., Wang, W., Shi, T., Zheng, Y., Lian, J., et al. (2025) · Nature Cell Biology · doi:10.1038/s41556-025-01737-3 · Cited by 5 · see citing works
“2c), while normal brain-specific motifs were associated with genomic stability factors such as RUNX3 33–35 and E2F7 36,37 (Extended Data Fig.”
Comprehensive bioinformatics analysis of the E2F family in human clear cell renal cell carcinoma
Liu, Z.-G., Su, J., Liu, H., Yang, X., Yang, X., Wei, Y., Zhu, X., Song, Y., Zhao, X., & Guo, H. (2022) · Oncology Letters · doi:10.3892/ol.2022.13471 · Cited by 5 · see citing works
Wu, Y.-F., Yuan, J.-M., Tu, Z., & Chen, H.-L. (2022) · Journal of Oncology · doi:10.1155/2022/3744560 · Cited by 3
“When combined with the inhibition of E2F-dependent transcription in the S phase and DNA destruction reagent, the synergistic killing of cancer can be achieved [32].”
BackgroundJin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., & Nusse, R. (2021) · doi:10.1101/2021.10.15.464616 · Cited by 2 · see citing works
“Interestingly, activating mutations in Wnt signaling components are common in liver cancer (Nusse and Clevers 2017; Wang et al. 2019) while E2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis (Kent et al. 2016; Moreno et al. 2021; Wilkinson et al. 2019; Zhang et al. 2018).”
BackgroundFujita, K., Okamura, Y., Hayashi, M., Ashida, R., Otsu, T., Sakai, A., Mii, S., Sugimoto, M., Yamamoto, N., Toyama, H., et al. (2025) · Annals of Surgical Oncology · doi:10.1245/s10434-025-18912-3 · Cited by 2
Mishra, S., Sivanantham, A., Das, A., Gupta, P., Mahapatra, S. K., Thimmulappa, R., Ramalingam, S., Botlagunta, M., & Rajasekaran, S. (2025) · Journal of Applied Toxicology · doi:10.1002/jat.4964 · Cited by 2 · see citing works
“…et al. 2020), gallbladder (Ye et al. 2018), and lung adenocarcinoma (Lin et al. 2024), whereas other investigators demonstrated that E2F7 inhibits hepatocarcinoma (Moreno et al. 2021) and stress-induced skin cancer (Thurlings et al. 2017), indicating the functional role of E2F7 is controversial.”
Gao, S.-F., Zuo, K., Feng, L., Cao, H.-L., Jiao, X., Ma, C., Zhang, Q.-M., & Li, J. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116846 · Cited by 1
Ma, X., Huang, T.-D., Song, Y.-J., Pan, H.-Y., Du, A., Zhou, X.-Y., Zeng, Y., & Yuan, K.-F. (2025) · PLoS ONE · doi:10.1371/journal.pone.0323708 · Cited by 1
“Dysregulation of these genes is linked to HBV-induced liver carcinogenesis[46].”
Zhang, Y., Lu, Y., Wang, N., Hao, F., Chen, Y., Fei, X., & Wang, J. (2025) · The FASEB Journal · doi:10.1096/fj.202402520r
“Transcription factor KLF13 is upstream of Anillin and is definitely overexpressed in HCC.”
InfluentialJiang, Z., Yue, Z., Liang, J.-L., Yang, Y.-C., Zhao, Y., Chen, Y., Bai, L., Wang, R.-Q., Li, S.-H., & Lin, Y.-F. (2026) · Small · doi:10.1002/smll.74557
Das, A., Bhandari, S., Pal, H., Ramalingam, S., & Rajasekaran, S. (2026) · Journal of Applied Toxicology · doi:10.1002/jat.70290
Barbosa, M. G., Vos, D., Verzijl, C. R. C., Heida, A., Bakker, M., Kloosterhuis, N., Koster, M. H., Smit, M., Fajardo, A., Struik, D., et al. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2026.101788
Self-citationCorrelation between E2F7 overexpression and immune infiltration in lung adenocarcinoma
Gao, X.-T., Zhao, C., Wang, S., & Li, J.-X. (2026) · Discover Oncology · doi:10.1007/s12672-026-04966-6
“However, E2F7 has been reported to act as a potent suppressor of liver tumor growth in adult mice, which stands in sharp contrast to its oncogenic role observed in our lung adenocarcinoma study [8].”
Systematic analysis of the prognosis and immune infiltration of E2Fs in thyroid carcinoma
Fu, X., Zhou, X., Ji, F., He, Q., & Qiu, X.-G. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1215984
“This is in agreement with the findings of many previous research studies (Garneau et al., 2009; Fang et al., 2018; Moreno et al., 2021).”
BackgroundResult
- Authors
- Moreno, E., Toussaint, M. J. M., van Essen, S. C., Bongiovanni, L., van Liere, E. A., Koster, M. H., Yuan, R., van Deursen, J. M., Westendorp, B., & de Bruin, A.
- Affiliations
- Utrecht University (NL)
- Department of Biomolecular Health Sciences,Faculty of Veterinary Medicine,Utrecht University,Utrecht,the Netherlands
- University Medical Center Groningen (NL)
- Department of Biochemistry and Molecular Biology,Mayo Clinic,Rochester,MN
- Venue
- Hepatology
- Published
- 2021-01
- Volume
- 73
- Issue
- 1
- Pages
- 303-317
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC7898887
- OpenAlex
- W3014330773
- Cited by
- 37
- References
- 41
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 5 · 2020: 1
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- UniTERAMO Research Catalog (University of Teramo) (submittedVersion)
- Funders
- ZonMw (91116011)
- Universiteit Utrecht
- National Cancer Institute (R01CA096985)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- E2F7, E2F8, liver tumors, hepatocellular carcinoma, diethylnitrosamine-induced liver cancer, replication stress, DNA damage, apoptosis, cell proliferation, cell cycle regulation, transgenic mice, doxycycline-inducible expression, cancer therapy
- MeSH terms
- Animals, Cell Cycle, DNA Damage, HeLa Cells, Humans, Liver Neoplasms, Male, Mice, Inbred C57BL, Repressor Proteins, Transcriptional Activation, Apoptosis, Mice, Knockout, Hepatocytes, Cell Proliferation, E2F7 Transcription Factor, Mice
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