Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling

Oncogene volume 39, pages 1665–1680 (2020)Cite this article

Subjects

A Correction to this article was published on 03 February 2020

This article has been updated

Abstract

Discerning oncogenic drivers from passengers remain a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), which is the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. Genome-wide identification of the transcriptional targets of the ZNF774/NuRD complex by ChIP-seq indicated that ZNF774 represses a cohort of genes including NOTCH2 that are critically involved in the growth and mobility of HCC. We demonstrated that the ZNF774/NuRD complex inhibits the proliferation and invasion of HCC cells in vitro and suppresses HCC growth and metastasis in vivo. Importantly, the expression of ZNF774 is significantly downregulated in HCC, and low ZNF774 expression strongly correlated with high NOTCH2 expression, advanced pathological stages, and poor overall survival of the patients. Together, these results uncover a key role for the ZNF774/NuRD-NOTCH2 axis in hepatocarcinogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Change history

References

  1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76. https://doi.org/10.1053/j.gastro.2007.2504.2061.

    Article  CAS  PubMed  Google Scholar 

  2. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14. https://doi.org/10.1016/S0140-6736(1318)30010-30012.

    Article  Google Scholar 

  3. Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S, et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature. 2011;473:230–3. https://doi.org/10.1038/nature09999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Koch U, Radtke F. Notch and cancer: a double-edged sword. Cell Mol Life Sci. 2007;64:2746–62. https://doi.org/10.1007/s00018-00007-07164-00011.

    Article  CAS  PubMed  Google Scholar 

  5. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–33. https://doi.org/10.1016/j.cell.2009.1003.1045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, et al. Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development. 2001;128:491–502.

    Article  CAS  Google Scholar 

  7. Serra H, Chivite I, Angulo-Urarte A, Soler A, Sutherland JD, Arruabarrena-Aristorena A, et al. PTEN mediates Notch-dependent stalk cell arrest in angiogenesis. Nat Commun. 2015;6:7935. https://doi.org/10.1038/ncomms8935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Suzuki IK, Gacquer D, Van Heurck R, Kumar D, Wojno M, Bilheu A, et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through delta/notch regulation. Cell. 2018;173:1370–.e1316. https://doi.org/10.1016/j.cell.2018.1303.1067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xiao W, Gao Z, Duan Y, Yuan W, Ke Y. Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma. J Exp Clin Cancer Res. 2017;36:41. https://doi.org/10.1186/s13046-13017-10507-13043.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.

    Article  CAS  Google Scholar 

  11. Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci. 2013;126:2135–40. https://doi.org/10.1242/jcs.127308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dill MT, Tornillo L, Fritzius T, Terracciano L, Semela D, Bettler B, et al. Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology. 2013;57:1607–19. https://doi.org/10.1002/hep.26165.

    Article  CAS  PubMed  Google Scholar 

  13. Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 2008;48:607–16. https://doi.org/10.1002/hep.22381.

    Article  CAS  PubMed  Google Scholar 

  14. Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;97:1235–94. https://doi.org/10.1152/physrev.00005.02017.

    Article  CAS  PubMed  Google Scholar 

  15. Wang J, Dong M, Xu Z, Song X, Zhang S, Qiao Y, et al. Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene. 2018;37:3229–42. https://doi.org/10.1038/s41388-41018-40188-41381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huntzicker EG, Hotzel K, Choy L, Che L, Ross J, Pau G, et al. Differential effects of targeting Notch receptors in a mouse model of liver cancer. Hepatology. 2015;61:942–52.

    Article  CAS  Google Scholar 

  17. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.

    Article  CAS  Google Scholar 

  18. Totaro A, Castellan M, Di Biagio D, Piccolo S. Crosstalk between YAP/TAZ and Notch Signaling. Trends Cell Biol. 2018;28:560–73.

    Article  CAS  Google Scholar 

  19. Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–73.

    Article  CAS  Google Scholar 

  20. Huntzicker EG, Hotzel K, Choy L, Che L, Ross J, Pau G, et al. Differential effects of targeting Notch receptors in a mouse model of liver cancer. Hepatology. 2015;61:942–52. https://doi.org/10.1002/hep.27566.

    Article  CAS  PubMed  Google Scholar 

  21. Hayashi T, Gust KM, Wyatt AW, Goriki A, Jager W, Awrey S, et al. Not all NOTCH Is created equal: the oncogenic role of NOTCH2 in bladder cancer and its implications for targeted therapy. Clin Cancer Res. 2016;22:2981–92. https://doi.org/10.1158/1078-0432.CCR-2915-2360.

    Article  CAS  PubMed  Google Scholar 

  22. Hubmann R, Sieghart W, Schnabl S, Araghi M, Hilgarth M, Reiter M, et al. Gliotoxin targets nuclear NOTCH2 in human solid tumor derived cell lines in vitro and inhibits melanoma growth in xenograft mouse model. Front Pharm. 2017;8:319. https://doi.org/10.3389/fphar.2017.00319.

    Article  CAS  Google Scholar 

  23. Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010;464:1052–7. https://doi.org/10.1038/nature08878.

    Article  CAS  PubMed  Google Scholar 

  24. Beel AJ, Sanders CR. Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci. 2008;65:1311–34. https://doi.org/10.1007/s00018-00008-07462-00012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 2008;9:377–83. https://doi.org/10.1038/embor.2008.1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shih IeM, Wang TL. Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 2007;67:1879–82. https://doi.org/10.1158/0008-5472.CAN-1806-3958.

    Article  CAS  PubMed  Google Scholar 

  27. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435:959–63. https://doi.org/10.1038/nature03659.

    Article  CAS  PubMed  Google Scholar 

  28. Urrutia R. KRAB-containing zinc-finger repressor proteins. Genome Biol. 2003;4:231. https://doi.org/10.1186/gb-2003-1184-1110-1231.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gebelein B, Fernandez-Zapico M, Imoto M, Urrutia R. KRAB-independent suppression of neoplastic cell growth by the novel zinc finger transcription factor KS1. J Clin Invest. 1998;102:1911–9. https://doi.org/10.1172/JCI1919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Knight RD, Shimeld SM. Identification of conserved C2H2 zinc-finger gene families in the Bilateria. Genome Biol. 2001;2:RESEARCH0016.

    Article  CAS  Google Scholar 

  31. Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18:128–34. https://doi.org/10.1038/nrc.2017.1118.

    Article  CAS  PubMed  Google Scholar 

  32. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21:998–1009. https://doi.org/10.1038/nm.3902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016;166:21–45. https://doi.org/10.1016/j.cell.2016.1006.1028.

    Article  CAS  Google Scholar 

  34. Ong HT, Federspiel MJ, Guo CM, Ooi LL, Russell SJ, Peng KW, et al. Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth. J Hepatol. 2013;59:999–1006. https://doi.org/10.1016/j.jhep.2013.1007.1010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Si W, Huang W, Zheng Y, Yang Y, Liu X, Shan L, et al. Dysfunction of the reciprocal feedback loop between GATA3- and ZEB2-nucleated repression programs contributes to breast cancer metastasis. Cancer Cell. 2015;27:822–36. https://doi.org/10.1016/j.ccell.2015.1004.1011.

    Article  CAS  PubMed  Google Scholar 

  36. Jung KH, Zhang J, Zhou C, Shen H, Gagea M, Rodriguez-Aguayo C, et al. Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis. Hepatology. 2016;63:864–79. https://doi.org/10.1002/hep.28367.

    Article  CAS  PubMed  Google Scholar 

  37. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19:222–32. https://doi.org/10.1038/s41590-41018-40044-z.

    Article  CAS  PubMed  Google Scholar 

  38. Lorsch ZS, Hamilton PJ, Ramakrishnan A, Parise EM, Salery M, Wright WJ, et al. Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex. Nat Neurosci. 2019;22:1413–23. https://doi.org/10.1038/s41593-41019-40462-41598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology. 2015;61:382–92.

    Article  CAS  Google Scholar 

  40. Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, et al. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet. 2014;46:886–90. https://doi.org/10.1038/ng.3041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Capra JA, Erwin GD, McKinsey G, Rubenstein JL, Pollard KS. Many human accelerated regions are developmental enhancers. Philos Trans R Soc Lond B Biol Sci. 2013;368:20130025. https://doi.org/10.1098/rstb.2013.0025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Krushkal J, Ferrell R, Mockrin SC, Turner ST, Sing CF, Boerwinkle E. Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation. 1999;99:1407–10.

    Article  CAS  Google Scholar 

  43. Goriki A, Seiler R, Wyatt AW, Contreras-Sanz A, Bhat A, Matsubara A, et al. Unravelling disparate roles of NOTCH in bladder cancer. Nat Rev Urol. 2018;15:345–57. https://doi.org/10.1038/s41585-41018-40005-41581.

    Article  CAS  PubMed  Google Scholar 

  44. Totaro A, Castellan M, Di Biagio D, Piccolo S. Crosstalk between YAP/TAZ and Notch signaling. Trends Cell Biol. 2018;28:560–73. https://doi.org/10.1016/j.tcb.2018.1003.1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu N, Nguyen Q, Wan Y, Zhou T, Venter J, Frampton GA, et al. The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab Invest. 2017;97:843–53. https://doi.org/10.1038/labinvest.2017.1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. He L, Liu X, Yang J, Li W, Liu S, Liu X, et al. Imbalance of the reciprocally inhibitory loop between the ubiquitin-specific protease USP43 and EGFR/PI3K/AKT drives breast carcinogenesis. Cell Res. 2018;28:934–51. https://doi.org/10.1038/s41422-41018-40079-41426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li W, Zhang Z, Liu X, Cheng X, Zhang Y, Han X, et al. The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J Clin Invest. 2017;127:3421–40. https://doi.org/10.1172/JCI94233.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This paper was supported by Capital Health Research and Special Development (No. 2016-1-1111), National Key Technologies R&D Program (No. 2015BAI13B09), Beijing Municipal Administration of Hospitals Incubator Program (No. PX2016001 and No. PX2019004) and “Miaopu” Innovation Foundation of the Chinese PLA General Hospital (No. 17KMM07).

Author information

Authors and Affiliations

  1. General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Chengjian Guan

  2. Medical School of Chinese People’s Liberation Army, Beijing, 100853, China

    Chengjian Guan, Zhenyu Chang, Xinjin Gu & Rong Liu

  3. Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese People’s Liberation Army General Hospital, Beijing, 100853, China

    Chengjian Guan, Zhenyu Chang, Xinjin Gu & Rong Liu

  4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Lin He & Jing Liang

Authors
  1. Chengjian Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenyu Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinjin Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rong Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, C., He, L., Chang, Z. et al. ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling. Oncogene 39, 1665–1680 (2020). https://doi.org/10.1038/s41388-019-1075-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-1075-0

This article is cited by

Search

Advanced search

Quick links