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.

  • Original Article
  • Published:

Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation

Oncogene volume 36, pages 6262–6271 (2017)Cite this article

Subjects

Abstract

Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  PubMed  Google Scholar 

  2. Forner A, Llovet JM, Bruix J . Hepatocellular carcinoma. Lancet 2012; 379: 1245–1255.

    Article  PubMed  Google Scholar 

  3. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM . The genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 2015; 149: 1226–1239.

    Article  CAS  PubMed  Google Scholar 

  4. 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: 1267–1273.

    Article  CAS  PubMed  Google Scholar 

  5. Mínguez B, Tovar V, Chiang D, Villanueva A, Llovet JM . Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 2009; 25: 186–194.

    Article  PubMed  Google Scholar 

  6. Kudo Y, Tanaka Y, Tateishi K, Yamamoto K, Yamamoto S, Mohri D et al. Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway. J Hepatol 2011; 55: 1400–1408.

    Article  CAS  PubMed  Google Scholar 

  7. Fruman DA, Rommel C . PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140–156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhu AX, Kudo M, Assenat E, Cattan S, Kang Y-K, Lim HY et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. Jama 2014; 312: 57–67.

    Article  PubMed  Google Scholar 

  9. Mann DA . Epigenetics in liver disease. Hepatology 2014; 60: 1418–1425.

    Article  CAS  PubMed  Google Scholar 

  10. Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet 2016; 48: 500–509.

    Article  CAS  PubMed  Google Scholar 

  11. Zeybel M, Mann DA, Mann J . Epigenetic modifications as new targets for liver disease therapies. J Hepatol 2013; 59: 1349–1353.

    Article  PubMed  Google Scholar 

  12. Bitzer M, Horger M, Giannini EG, Ganten TM, Wörns MA, Siveke JT et al. Resminostat in combination with sorafenib as second-line therapy of advanced hepatocellular carcinoma—The SHELTER Study. J Hepatol 2016; 65: 280–288.

    Article  CAS  PubMed  Google Scholar 

  13. Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 2006; 125: 483–495.

    Article  CAS  PubMed  Google Scholar 

  14. Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y . Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 2007; 450: 119–123.

    Article  CAS  PubMed  Google Scholar 

  15. Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N et al. Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 2013; 341: 1106–1109.

    Article  CAS  PubMed  Google Scholar 

  16. Tateishi K, Okada Y, Kallin EM, Zhang Y . Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 2009; 458: 757–761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Inagaki T, Tachibana M, Magoori K, Kudo H, Tanaka T, Okamura M et al. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes Cells 2009; 14: 991–1001.

    Article  CAS  PubMed  Google Scholar 

  18. Uemura M, Yamamoto H, Takemasa I, Mimori K, Hemmi H, Mizushima T et al. Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells. Clin Cancer Res 2010; 16: 4636–4646.

    Article  CAS  PubMed  Google Scholar 

  19. Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, Giaccia AJ . Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol 2010; 30: 344–353.

    Article  CAS  PubMed  Google Scholar 

  20. Osawa T, Tsuchida R, Muramatsu M, Shimamura T, Wang F, Suehiro JI et al. Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. Cancer Res 2013; 73: 3019–3028.

    Article  CAS  PubMed  Google Scholar 

  21. Fan L, Peng G, Sahgal N, Fazli L, Gleave M, Zhang Y et al. Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival. Oncogene 2015; 24: 414–418.

    Google Scholar 

  22. Yamada D, Kobayashi S, Yamamoto H, Tomimaru Y, Noda T, Uemura M et al. Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. Ann Surg Oncol 2012; 19 (Suppl 3): S355–S364.

    Article  PubMed  Google Scholar 

  23. Park SJ, Kim JG, Son TG, Yi JM, Kim ND, Yang K et al. The histone demethylase JMJD1A regulates adrenomedullin-mediated cell proliferation in hepatocellular carcinoma under hypoxia. Biochem Biophys Res Commun 2013; 434: 722–727.

    Article  CAS  PubMed  Google Scholar 

  24. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Min L, Ji Y, Bakiri L, Qiu Z, Cen J, Chen X et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat Cell Biol 2012; 14: 1203–1211.

    Article  CAS  PubMed  Google Scholar 

  26. Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T et al. PID: the pathway interaction database. Nucleic Acids Res 2009; 37 (Database issue): D674–D679.

    Article  CAS  PubMed  Google Scholar 

  27. Eferl R, Wagner EF . AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 2003; 3: 859–868.

    Article  CAS  PubMed  Google Scholar 

  28. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008; 13: 153–166.

    Article  CAS  PubMed  Google Scholar 

  29. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359: 1995–2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Maass T, Thieringer FR, Mann A, Longerich T, Schirmacher P, Strand D et al. Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer 2011; 128: 1259–1268.

    Article  CAS  PubMed  Google Scholar 

  31. Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG . The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 2005; 8: 25–33.

    Article  CAS  PubMed  Google Scholar 

  32. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer 2010; 126: 2067–2078.

    Article  CAS  PubMed  Google Scholar 

  33. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Weglarz TC, Degen JL, Sandgren EP . Hepatocyte transplantation into diseased mouse liver. Am J Pathol 2000; 157: 1963–1974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013; 155: 384–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 2014; 26: 331–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Beyaz S, Mana MD, Roper J, Kedrin D, Saadatpour A, Hong SJ et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 2016; 531: 53–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamamoto S, Tateishi K, Kudo Y, Yamamoto K, Isagawa T, Nagae G et al. Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. Carcinogenesis 2013; 34: 2380–2388.

    Article  CAS  PubMed  Google Scholar 

  39. Ding X, Pan H, Li J, Zhong Q, Chen X, Dry SM et al. Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis. Sci Signal 2013; 6: ra28.1–13.

    Article  Google Scholar 

  40. Ramadoss S, Guo G, Wang CY . Lysine demethylase KDM3A regulates breast cancer cell invasion and apoptosis by targeting histone and the non-histone protein p53. Oncogene 2017; 36: 47–59.

    Article  CAS  PubMed  Google Scholar 

  41. Abe Y, Rozqie R, Matsumura Y, Kawamura T, Nakaki R, Tsurutani Y et al. JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis. Nat Commun 2015; 6: 7052.

    Article  CAS  PubMed  Google Scholar 

  42. Ito T, Yamauchi M, Nishina M, Yamamichi N, Mizutani T, Ui M et al. Identification of SWI·SNF complex subunit BAF60a as a determinant of the transactivation potential of Fos/Jun dimers. J Biol Chem 2001; 276: 2852–2857.

    Article  CAS  PubMed  Google Scholar 

  43. Shakya A, Kang J, Chumley J, Williams MA, Tantin D . Oct1 is a switchable, bipotential stabilizer of repressed and inducible transcriptional states. J Biol Chem 2011; 286: 450–459.

    Article  CAS  PubMed  Google Scholar 

  44. Chu TH, Chan HH, Kuo HM, Liu LF, Hu TH, Sun CK et al. Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN. Oncotarget 2014; 5: 1475–1490.

    Article  PubMed  Google Scholar 

  45. Okabe H, Ishimoto T, Mima K, Nakagawa S, Hayashi H, Kuroki H et al. CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma. Br J Cancer 2014; 110: 958–966.

    Article  CAS  PubMed  Google Scholar 

  46. Nakagawa H, Hikiba Y, Hirata Y, Font-Burgada J, Sakamoto K, Hayakawa Y et al. Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis. Proc Natl Acad Sci USA 2014; 111: 1090–1095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tam WL, Lu H, Buikhuisen J, Soh BS, Lim E, Reinhardt F et al. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 2013; 24: 347–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Llovet JM, Villanueva A, Lachenmayer A, Finn RS . Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 2015; 12: 408–424.

    Article  CAS  PubMed  Google Scholar 

  49. Xin HW, Ambe CM, Hari DM, Wiegand GW, Miller TC, Chen JQ et al. Label-retaining liver cancer cells are relatively resistant to sorafenib. Gut 2013; 62: 1777–1786.

    Article  CAS  PubMed  Google Scholar 

  50. Hasenfuss SC, Bakiri L, Thomsen MK, Williams EG, Auwerx J, Wagner EF . Regulation of steatohepatitis and PPARγ signaling by distinct AP-1 dimers. Cell Metab 2014; 19: 84–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yamamoto K, Tateishi K, Kudo Y, Sato T, Yamamoto S, Miyabayashi K et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. Carcinogenesis 2014; 35: 2404–2414.

    Article  CAS  PubMed  Google Scholar 

  52. Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 2013; 494: 247–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedman JR, Larris B, Le PP, Peiris TH, Arsenlis A, Schug J et al. Orthogonal analysis of C/EBPbeta targets in vivo during liver proliferation. Proc Natl Acad Sci USA 2004; 101: 12986–12991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This project is supported by Grants-in-Aid for Scientific Research (23590962) from Japan Society for the Promotion of Science, the grant from New Energy and Industrial Technology Development Organization (NEDO), and the Research Program on Hepatitis from Japan Agency for Medical Research and Development (AMED). We thank Dr E.P. Sandgren for MUP-uPA mice, Mitsuko Tsubouchi for providing assistance with various cell cultures, and all the lab members for their helpful comments.

Author contributions

Study concept and design: TN, KT. Experiments and procedures: TN. Interpretation of data: TN, KT, YK, KY, RT, KM, YA, YT, HI, YH, MO. Technical and material support: KT, YK, KY, HN, HF, YT, MK, JS, MT, HA, YS. Drafting of the manuscript: TN. Revising of the manuscript: KT. Funding and study supervision: KT, HA, KK. Editing and reviewing of the final manuscript: all authors.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    T Nakatsuka, K Tateishi, Y Kudo, K Yamamoto, H Nakagawa, H Fujiwara, R Takahashi, K Miyabayashi, Y Asaoka, Y Tanaka, H Ijichi, Y Hirata, M Otsuka & K Koike

  2. Cellular Memory Laboratory, RIKEN Advanced Science Institute, Wako-shi, Saitama, Japan

    M Kato & Y Shinkai

  3. Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Meguro-ku,, Tokyo, Japan

    J Sakai

  4. Department of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima-shi, Tokushima, Japan

    M Tachibana

  5. Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Meguro-ku, Tokyo, Japan

    H Aburatani

Authors
  1. T Nakatsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Tateishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Miyabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Asaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Ijichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Tachibana
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. H Aburatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Y Shinkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. K Koike
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Tateishi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakatsuka, T., Tateishi, K., Kudo, Y. et al. Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation. Oncogene 36, 6262–6271 (2017). https://doi.org/10.1038/onc.2017.222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.222

This article is cited by

Search

Advanced search

Quick links