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:

Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling

Oncogene volume 34, pages 3188–3198 (2015)Cite this article

Subjects

A Corrigendum to this article was published on 11 June 2015

This article has been updated

Abstract

Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5+ HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5+ cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5+ CICs. Mechanistically, LSD1 promotes β-catenin activation by inhibiting the expression of several suppressors of β-catenin signaling, especially Prickle1 and APC in Lgr5+ CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the β-catenin signaling is essential for maintaining the activity of Lgr5+ CICs. Together, our findings unravel the LSD1/Prickle1/APC/β-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5+ CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.

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
Figure 7

Similar content being viewed by others

Change history

  • 11 June 2015

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue.

References

  1. Yamashita T, Wang XW . Cancer stem cells in the development of liver cancer. J Clin Invest 2013; 123: 1911–1918.

    Article  CAS  Google Scholar 

  2. Meacham CE, Morrison SJ . Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501: 328–337.

    Article  CAS  Google Scholar 

  3. Wang Z, Wang B, Shi Y, Xu C, Xiao HL, Ma LN et al. Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2. Oncogene 2015; 34: 1407–1419.

    Article  CAS  Google Scholar 

  4. Wang B, Wang Q, Wang Z, Jiang J, Yu SC, Ping YF et al. Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Cancer Res 2014; 74: 5746–5757.

    Article  CAS  Google Scholar 

  5. Huch M, Dorrell C, Boj SF, van Es JH, Li VS, 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  Google Scholar 

  6. Hu M, Kurobe M, Jeong YJ, Fuerer C, Ghole S, Nusse R et al. Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology 2007; 133: 1579–1591.

    Article  CAS  Google Scholar 

  7. Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 2008; 68: 4287–4295.

    Article  CAS  Google Scholar 

  8. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 2010; 6: 25–36.

    Article  CAS  Google Scholar 

  9. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003–1007.

    Article  CAS  Google Scholar 

  10. Qiu W, Wang X, Buchanan M, He K, Sharma R, Zhang L et al. ADAR1 is essential for intestinal homeostasis and stem cell maintenance. Cell Death Dis 2013; 4: e599.

    Article  CAS  Google Scholar 

  11. Hirsch D, Barker N, McNeil N, Hu Y, Camps J, McKinnon K et al. LGR5 positivity defines stem-like cells in colorectal cancer. Carcinogenesis 2014; 35: 849–858.

    Article  CAS  Google Scholar 

  12. Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 2012; 337: 730–735.

    Article  CAS  Google Scholar 

  13. Kemper K, Prasetyanti PR, De Lau W, Rodermond H, Clevers H, Medema JP . Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells 2012; 30: 2378–2386.

    Article  CAS  Google Scholar 

  14. Fukuma M, Tanese K, Effendi K, Yamazaki K, Masugi Y, Suda M et al. Leucine-rich repeat-containing G protein-coupled receptor 5 regulates epithelial cell phenotype and survival of hepatocellular carcinoma cells. Exp Cell Res 2013; 319: 113–121.

    Article  CAS  Google Scholar 

  15. Greer EL, Shi Y . Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012; 13: 343–357.

    Article  CAS  Google Scholar 

  16. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 2009; 138: 660–672.

    Article  CAS  Google Scholar 

  17. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004; 119: 941–953.

    Article  CAS  Google Scholar 

  18. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005; 437: 436–439.

    Article  CAS  Google Scholar 

  19. Adamo A, Sese B, Boue S, Castano J, Paramonov I, Barrero MJ et al. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol 2011; 13: 652–659.

    Article  CAS  Google Scholar 

  20. Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 2011; 71: 7238–7249.

    Article  CAS  Google Scholar 

  21. Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 2012; 21: 473–487.

    Article  CAS  Google Scholar 

  22. Zhao ZK, Dong P, Gu J, Chen L, Zhuang M, Lu WJ et al. Overexpression of LSD1 in hepatocellular carcinoma: a latent target for the diagnosis and therapy of hepatoma. Tumour Biol 2013; 34: 173–180.

    Article  Google Scholar 

  23. Yu Y, Wang B, Zhang K, Lei Z, Guo Y, Xiao H et al. High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma. Biochem Biophys Res Commun 2013; 437: 192–198.

    Article  CAS  Google Scholar 

  24. Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer 2011; 128: 574–586.

    Article  CAS  Google Scholar 

  25. Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med 2014; 20: 29–36.

    Article  CAS  Google Scholar 

  26. Shan J, Shen J, Liu L, Xia F, Xu C, Duan G et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology 2012; 56: 1004–1014.

    Article  CAS  Google Scholar 

  27. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO . CD24+ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 2011; 9: 50–63.

    Article  CAS  Google Scholar 

  28. Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest 2010; 120: 3326–3339.

    Article  CAS  Google Scholar 

  29. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009; 136: 1012–1024.

    Article  CAS  Google Scholar 

  30. Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 2007; 132: 2542–2556.

    Article  CAS  Google Scholar 

  31. O'Brien CA, Kreso A, Ryan P, Hermans KG, Gibson L, Wang Y et al. ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell 2012; 21: 777–792.

    Article  CAS  Google Scholar 

  32. Chan DW, Chan CY, Yam JW, Ching YP, Ng IO . Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer. Gastroenterology 2006; 131: 1218–1227.

    Article  CAS  Google Scholar 

  33. Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 2013; 500: 222–226.

    Article  CAS  Google Scholar 

  34. Wang B, Liu J, Ma LN, Xiao HL, Wang YZ, Li Y et al. Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44+ gastric cancer cells via attenuating Wnt signaling. J Gastroenterol 2013; 48: 798–808.

    Article  CAS  Google Scholar 

  35. Plaks V, Brenot A, Lawson DA, Linnemann JR, Van Kappel EC, Wong KC et al. Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep 2013; 3: 70–78.

    Article  CAS  Google Scholar 

  36. Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G, Nikitin AY . Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature 2013; 495: 241–245.

    Article  CAS  Google Scholar 

  37. Gil-Sanchis C, Cervello I, Mas A, Faus A, Pellicer A, Simon C . Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. Mol Hum Reprod 2013; 19: 407–414.

    Article  CAS  Google Scholar 

  38. Xi HQ, Cai AZ, Wu XS, Cui JX, Shen WS, Bian SB et al. Leucine-rich repeat-containing G-protein-coupled receptor 5 is associated with invasion, metastasis, and could be a potential therapeutic target in human gastric cancer. Br J Cancer 2014; 110: 2011–2020.

    Article  CAS  Google Scholar 

  39. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011; 43: 34–41.

    Article  CAS  Google Scholar 

  40. 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  Google Scholar 

  41. Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y et al. Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology 2013; 57: 1484–1497.

    Article  CAS  Google Scholar 

  42. Ding J, Zhang ZM, Xia Y, Liao GQ, Pan Y, Liu S et al. LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br J Cancer 2013; 109: 994–1003.

    Article  CAS  Google Scholar 

  43. Qin Y, Zhu W, Xu W, Zhang B, Shi S, Ji S et al. LSD1 sustains pancreatic cancer growth via maintaining HIF1alpha-dependent glycolytic process. Cancer Lett 2014; 347: 225–232.

    Article  CAS  Google Scholar 

  44. Suva ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 2014; 157: 580–594.

    Article  CAS  Google Scholar 

  45. Wu Y, Wang Y, Yang XH, Kang T, Zhao Y, Wang C et al. The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells. Cell Rep 2013; 5: 224–236.

    Article  CAS  Google Scholar 

  46. Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 2012; 18: 605–611.

    Article  CAS  Google Scholar 

  47. Zhang X, Lu F, Wang J, Yin F, Xu Z, Qi D et al. Pluripotent stem cell protein Sox2 confers sensitivity to LSD1 inhibition in cancer cells. Cell Rep 2013; 5: 445–457.

    Article  CAS  Google Scholar 

  48. Huang Z, Li S, Song W, Li X, Li Q, Zhang Z et al. Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/Beta-catenin pathway by down-regulating Dickkopf-1 (DKK1). PLoS One 2013; 8: e70077.

    Article  CAS  Google Scholar 

  49. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–390.

    Article  CAS  Google Scholar 

  50. Wang B, Yu SC, Jiang JY, Porter GW, Zhao LT, Wang Z et al. An inhibitor of arachidonate 5-lipoxygenase, Nordy, induces differentiation and inhibits self-renewal of glioma stem-like cells. Stem Cell Rev 2011; 7: 458–470.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are indebted to Prof Xiang Xu (Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China) for his technical assistance. We are grateful to Miss Chunhua Quan, Ya Li and Qing Li (Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China) for their help in collecting clinical data. This work was supported by the grants from the National Natural Science Foundation of China (NSFC Nos. 81472294, 81201949, and 81372558), the Natural Science Foundation Project of CQ CSTC (No. CSTC2012JJA10124), and the Science Foundation of Third Military Medical University (No. 2012XJQ22).

Author information

Author notes

  1. Z-J Lei and J Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China,

    Z-J Lei, J Wang, Y Guo, T Wang, Q Li, L Liu, X Luo, L-L Fan, Y-L Wei, C-H Lan, D-F Chen & B Wang

  2. Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China,

    H-L Xiao, L Lin & C-Y Mao

  3. Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China,

    S-N Wang

  4. Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China,

    J Jiang

  5. Center for Neuroscience, Shantou University Medical College, Shantou, China

    X-J Yang

  6. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    P-D Liu

Authors
  1. Z-J Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H-L Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. X Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L-L Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C-Y Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S-N Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Y-L Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. C-H Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. X-J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. P-D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. D-F Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. B Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to D-F Chen or B Wang.

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

Lei, ZJ., Wang, J., Xiao, HL. et al. Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling. Oncogene 34, 3188–3198 (2015). https://doi.org/10.1038/onc.2015.129

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.129

This article is cited by

Search

Advanced search

Quick links