Skip to main content

Advertisement

SpringerLink
Log in

Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Hypoxia is commonly found in human solid cancers and serves as a selective environment for the survival of aggressive cancer cells and as protection from anti-cancer therapies. In addition to a shift to anaerobic metabolism, the cellular response to hypoxia includes cessation of cell division and/or cell death. These mechanisms have still not been defined. Identification of the members of hypoxia-induced growth arrest pathways remain incomplete. We have undertaken an expression microarray analysis of the cellular response to hypoxia in diverse cell lines. An identified cohort of genes is reliably upregulated in various cells in response to hypoxia, as validated by reverse-transcriptase polymerase chain reaction (RT-PCR). One of the upregulated targets corresponds to an expressed sequence tag encoded by JMJD1A (a gene also known as JHDM2A), which has been identified as a histone demethylase that regulates the transcription of androgen receptor targets. We confirm, by RT-PCR, the upregulation of JMJD1A after hypoxia and desferroxamine treatment in multiple cell lines. We also show that JMJD1A is predominantly, but not exclusively, a nuclear protein. Immunofluorescent staining of HeLa cells shows a shift of cytoplasmic JMJD1A into the nucleus on hypoxia treatment. Immunohistochemical staining has revealed that JMJD1A is widely expressed in tissues, even in cells that are not known to express the androgen receptor, and is significantly increased in smooth muscle cells upon hypoxia treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Amellem O, Pettersen EO (1991) Cell inactivation and cell cycle inhibition as induced by extreme hypoxia: the possible role of cell cycle arrest as a protection against hypoxia-induced lethal damage. Cell Prolif 24:127–141

    Article  PubMed  CAS  Google Scholar 

  • Bando H, Toi M, Kitada K, Koike M (2003) Genes commonly upregulated by hypoxia in human breast cancer cells MCF-7 and MDA-MB-231. Biomed Pharmacother 57:333–340

    Article  PubMed  CAS  Google Scholar 

  • Beilharz EJ, Bassett NS, Sirimanne ES, Williams CE, Gluckman PD (1995) Insulin-like growth factor II is induced during wound repair following hypoxic-ischemic injury in the developing rat brain. Brain Res Mol Brain Res 29:81–91

    Article  PubMed  CAS  Google Scholar 

  • Beitner-Johnson D, Seta K, Yuan Y, Kim H, Rust RT, Conrad PW, Kobayashi S, Millhorn DE (2001) Identification of hypoxia-responsive genes in a dopaminergic cell line by subtractive cDNA libraries and microarray analysis. Parkinsonism Relat Disord 7:273–281

    Article  PubMed  Google Scholar 

  • Box AH, Yuen C, Ponjevic D, Fick GH, Demetrick DJ (2008) Signaling and apoptosis differences between severe hypoxia and desferoxamine treatment of human epithelial cells. Biochem Cell Biol 86:425-436

    Article  PubMed  CAS  Google Scholar 

  • Cangul H (2004) Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet 5:27

    Article  PubMed  Google Scholar 

  • Ebert BL, Firth JD, Ratcliffe PJ (1995) Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 270:29083–29089

    Article  PubMed  CAS  Google Scholar 

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    PubMed  CAS  Google Scholar 

  • Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ (1988) Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14:831–838

    PubMed  CAS  Google Scholar 

  • Gleadle JM, Ebert BL, Firth JD, Ratcliffe PJ (1995) Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am J Physiol 268:C1362–C1368

    PubMed  CAS  Google Scholar 

  • Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91

    Article  PubMed  CAS  Google Scholar 

  • Green SL, Giaccia AJ (1998) Tumor hypoxia and the cell cycle: implications for malignant progression and response to therapy. Cancer J Sci Am 4:218–223

    PubMed  CAS  Google Scholar 

  • Green SL, Freiberg RA, Giaccia AJ (2001) p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest. Mol Cell Biol 21:1196–1206

    Article  PubMed  CAS  Google Scholar 

  • Hoog C, Schalling M, Grunder-Brundell E, Daneholt B (1991) Analysis of a murine male germ cell-specific transcript that encodes a putative zinc finger protein. Mol Reprod Dev 30:173–181

    Article  PubMed  CAS  Google Scholar 

  • Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992

    Article  PubMed  CAS  Google Scholar 

  • Knebel J, De Haro L, Janknecht R (2006) Repression of transcription by TSGA/Jmjd1a, a novel interaction partner of the ETS protein ER71. J Cell Biochem 99:319–329

    Article  PubMed  CAS  Google Scholar 

  • Koong AC, Denko NC, Hudson KM, Schindler C, Swiersz L, Koch C, Evans S, Ibrahim H, Le QT, Terris DJ, Giaccia AJ (2000) Candidate genes for the hypoxic tumor phenotype. Cancer Res 60:883–887

    PubMed  CAS  Google Scholar 

  • Krtolica A, Ludlow JW (1996) Hypoxia arrests ovarian carcinoma cell cycle progression, but invasion is unaffected. Cancer Res 56:1168–1173

    PubMed  CAS  Google Scholar 

  • Loh YH, Zhang W, Chen X, George J, Ng HH (2007) Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev 21:2545–2557

    Article  PubMed  CAS  Google Scholar 

  • McGraw S, Vigneault C, Sirard MA (2007) Temporal expression of factors involved in chromatin remodeling and in gene regulation during early bovine in vitro embryo development. Reproduction 133:597-608

    Article  PubMed  CAS  Google Scholar 

  • Minchenko O, Opentanova I, Caro J (2003) Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase gene family (PFKFB-1–4) expression in vivo. FEBS Lett 554:264–270

    Article  PubMed  CAS  Google Scholar 

  • Narravula S, Colgan SP (2001) Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol 166:7543–7548

    PubMed  CAS  Google Scholar 

  • O'Rourke JF, Pugh CW, Bartlett SM, Ratcliffe PJ (1996) Identification of hypoxically inducible mRNAs in HeLa cells using differential-display PCR. Role of hypoxia-inducible factor-1. Eur J Biochem 241:403–410

    Article  PubMed  Google Scholar 

  • Oexle H, Gnaiger E, Weiss G (1999) Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta 1413:99–107

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Park H, Adams MA, Lachat P, Bosman F, Pang SC, Graham CH (2000) Hypoxia induces the expression of a 43-kDa protein (PROXY-1) in normal and malignant cells. Biochem Biophys Res Commun 276:321–328

    Article  PubMed  CAS  Google Scholar 

  • Pollard PJ, Loenarz C, Mole D, McDonough MA, Gleadle JM, Schofield C, Ratcliffe PJ (2008) Regulation of Jumonji-domain containing histone demethylases by hypoxia inducible factor (HIF) 1-alpha. Biochem J 416:387–394

    Article  PubMed  CAS  Google Scholar 

  • Rolfs A, Kvietikova I, Gassmann M, Wenger RH (1997) Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem 272:20055–20062

    Article  PubMed  CAS  Google Scholar 

  • Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272:22642–22647

    CAS  Google Scholar 

  • Schwickert G, Walenta S, Sundfor K, Rofstad EK, Mueller-Klieser W (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 55:4757–4759

    PubMed  CAS  Google Scholar 

  • Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454

    PubMed  CAS  Google Scholar 

  • Seta KA, Millhorn DE (2004) Functional genomics approach to hypoxia signaling. J Appl Physiol 96:765–773

    Article  PubMed  CAS  Google Scholar 

  • Seta KA, Spicer Z, Yuan Y, Lu G, Millhorn DE (2002) Responding to hypoxia: lessons from a model cell line. Sci STKE 2002:RE11

    Article  PubMed  CAS  Google Scholar 

  • Sonna LA, Cullivan ML, Sheldon HK, Pratt RE, Lilly CM (2003) Effect of hypoxia on gene expression by human hepatocytes (HepG2). Physiol Genomics 12:195–207

    PubMed  CAS  Google Scholar 

  • Sung YJ, Denman RB (1997) Use of two reverse transcriptases eliminates false-positive results in differential display. Biotechniques 23:462-468

    PubMed  CAS  Google Scholar 

  • Tachibana M, Nozaki M, Takeda N, Shinkai Y (2007) Functional dynamics of H3K9 methylation during meiotic prophase progression. EMBO J 26:3346–3359

    Article  PubMed  CAS  Google Scholar 

  • Tomida A, Tsuruo T (1999) Drug resistance mediated by cellular stress response to the microenvironment of solid tumors. Anticancer Drug Des 14:169–177

    PubMed  CAS  Google Scholar 

  • Urbanucci A, Waltering KK, Suikki HE, Helenius MA, Visakorpi T (2008) Androgen regulation of the androgen receptor coregulators. BMC Cancer 8:219

    Article  PubMed  Google Scholar 

  • Wang GL, Semenza GL (1993a) Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 268:21513–21518

    PubMed  CAS  Google Scholar 

  • Wang GL, Semenza GL (1993b) Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82:3610–3615

    PubMed  CAS  Google Scholar 

  • Wellmann S, Buhrer C, Moderegger E, Zelmer A, Kirschner R, Koehne P, Fujita J, Seeger K (2004) Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism. J Cell Sci 117:1785–1794

    Article  PubMed  CAS  Google Scholar 

  • Wellmann S, Bettkober M, Zelmer A, Seeger K, Faigle M, Eltzschig HK, Buhrer C (2008) Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. Biochem Biophys Res Commun 372:892–897

    Article  PubMed  CAS  Google Scholar 

  • Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Erin MacRae and Claude Veillette for excellent technical assistance and Ponnampalam Thirukkumaran of the Southern Alberta Microarray Facility for performing the expression microarray hybridizations.

Author information

Authors and Affiliations

  1. The Departments of Pathology and Laboratory Medicine, Oncology, Biochemistry and Molecular Biology, and Medical Genetics, University of Calgary, Room 302, HMRB, 3330 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada

    Aylin Sar, Dragana Ponjevic, Monica Nguyen, Adrian Harold Box & Douglas James Demetrick

  2. Anatomical Pathology, Calgary Laboratory Services, Calgary, Canada

    Douglas James Demetrick

Authors
  1. Aylin Sar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dragana Ponjevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monica Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adrian Harold Box
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Douglas James Demetrick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas James Demetrick.

Additional information

The authors acknowledge funding from the Ruth Barker Foundation and from an Alberta Cancer Board Pilot Project grant (23289). A.S. was supported by the Division of Transplant Research, University of Calgary. Salary support for M.N. was provided by the Ruth Barker Foundation. Salary support for D.J.D. was provided by Calgary Laboratory Services. A.H.B. was supported by a stipend from the CIHR-Alberta Cancer Board Strategic Training Program in Translational Cancer Research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sar, A., Ponjevic, D., Nguyen, M. et al. Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia. Cell Tissue Res 337, 223–234 (2009). https://doi.org/10.1007/s00441-009-0805-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-009-0805-y

Keywords

Search

Navigation