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:

Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress

Oncogene volume 34, pages 4591–4600 (2015)Cite this article

Subjects

Abstract

Relapse after clinical remission remains a leading cause of cancer-associated death. Although the mechanisms of tumor relapse are complex, the ability of cancer cells to survive physiological stress is a prerequisite for recurrence. Ewing sarcoma (ES) and neuroblastoma (NB) are aggressive cancers that frequently relapse after initial remission. In addition, both tumors overexpress the polycomb group (PcG) proteins BMI-1 and EZH2, which contribute to tumorigenicity. We have discovered that ES and NB resist hypoxic stress-induced death and that survival depends on PcG function. Epigenetic repression of developmental programs is the most well-established cancer-associated function of PcG proteins. However, we noted that voltage-gated potassium (Kv) channel genes are also targets of PcG regulation in stem cells. Given the role of potassium in regulating apoptosis, we reasoned that repression of Kv channel genes might have a role in cancer cell survival. Here we describe our novel finding that PcG-dependent repression of the Kv1.5 channel gene KCNA5 contributes to cancer cell survival under conditions of stress. We show that survival of cancer cells in stress is dependent upon suppression of Kv1.5 channel function. The KCNA5 promoter is marked in cancer cells with PcG-dependent chromatin repressive modifications that increase in hypoxia. Genetic and pharmacological inhibition of BMI-1 and EZH2, respectively, restore KCNA5 expression, which sensitizes cells to stress-induced death. In addition, ectopic expression of the Kv1.5 channel induces apoptotic cell death under conditions of hypoxia. These findings identify a novel role for PcG proteins in promoting cancer cell survival via repression of KCNA5.

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. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  PubMed  Google Scholar 

  2. Bertout JA, Patel SA, Simon MC . The impact of O2 availability on human cancer. Nat Rev Cancer 2008; 8: 967–975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ito K, Suda T . Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 2014; 15: 243–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gupta PB, Chaffer CL, Weinberg RA . Cancer stem cells: mirage or reality? Nat Med 2009; 15: 1010–1012.

    Article  CAS  PubMed  Google Scholar 

  5. Laugesen A, Helin K . Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell 2014; 14: 735–751.

    Article  CAS  PubMed  Google Scholar 

  6. Bracken AP, Helin K . Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer 2009; 9: 773–784.

    Article  CAS  PubMed  Google Scholar 

  7. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66: 6063–6071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Douglas D, Abdueva D, van Doorninck J, Peng G, Shimada H, Tritche T . BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res 2008; 68: 6507–6515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nowak K, Kerl K, Fehr D, Kramps C, Gessner C, Killmer K et al. BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res 2006; 34: 1745–1754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Richter GH, Plehm S, Fasan A, Rössler S, Unland R, Bennani-Baiti IM et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci USA 2009; 106: 5324–5329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Riggi N, Suva M-L, Suva D, Cironi L, Provero P, Tercier S et al. EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res 2008; 68: 2176–2185.

    Article  CAS  PubMed  Google Scholar 

  12. Wang C, Liu Z, Woo C-W, Li Z, Wang L, Wei J et al. EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res 2012; 72: 315–324.

    Article  CAS  PubMed  Google Scholar 

  13. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006; 125: 301–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fraser SP, Ozerlat-Gunduz I, Brackenbury WJ, Fitzgerald EM, Campbell TM, Coombes RC et al. Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation. Philos Trans R Soc London Ser B Biol Sci 2014; 369: 20130105.

    Article  Google Scholar 

  15. Monteith GR, McAndrew D, Faddy HM, Roberts-Thomson SJ . Calcium and cancer: targeting Ca2+ transport. Nat Rev Cancer 2007; 7: 519–530.

    Article  CAS  PubMed  Google Scholar 

  16. Huang X, Jan LY . Targeting potassium channels in cancer. J Cell Biol 2014; 206: 151–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. von Levetzow C, Jiang X, Gwye Y, von Levetzow G, Hung L, Cooper A et al. Modeling initiation of Ewing sarcoma in human neural crest cells. PLoS ONE 2011; 6: e19305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2013; 492: 108–112.

    Article  Google Scholar 

  19. Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 2006; 20: 1123–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lang F, Hoffmann EK . Role of ion transport in control of apoptotic cell death. Compr Physiol 2012; 2: 2037–2061.

    PubMed  Google Scholar 

  21. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007; 11: 37–51.

    Article  CAS  PubMed  Google Scholar 

  22. Stapels M, Piper C, Yang T, Li M, Stowell C, Xiong Z-G et al. Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci Signal 2010; 3: ra15–ra15.

    Article  PubMed  Google Scholar 

  23. Cooper A, van Doorninck J, Ji L, Russell D, Ladanyi M, Shimada H et al. Ewing tumors that do not overexpress BMI-1 are a distinct molecular subclass with variant biology: a report from the Children's Oncology Group. Clin Cancer Res 2011; 17: 56–66.

    Article  CAS  PubMed  Google Scholar 

  24. Stump G, Wallace A, Regan C, Lynch J . In vivo antiarrhythmic and cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide. J Pharmacol Exp Ther 2005; 315: 1362–1367.

    Article  CAS  PubMed  Google Scholar 

  25. Fedida D, Bouchard R, Chen FSP . Slow gating charge immobilization in the human potassium channel Kv1.5 and its prevention by 4-aminopyridine. Am J Physiol Cell Physiol 1995; 494: 377–387.

    Article  Google Scholar 

  26. Schumacher SM, McEwen D, Zhang L, Arendt K, Van Genderen K, Martens JR . Antiarrhythmic drug-induced internalization of the atrial-specific K+ channel Kv1.5. Circ Res 2009; 104: 1390–1398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McEwen D, Schumacher SM, Li Q, Benson M, Iniguez-Lluhi J, Van Genderen K et al. Rab-GTPase-dependent endocytic recycling of KV1.5 in atrial myocytes. J Biol Chem 2007; 282: 29612–29620.

    Article  CAS  PubMed  Google Scholar 

  28. Burg ED, Remillard CV, Yuan JXJ . K+ channels in apoptosis. J Membr Biol 2006; 209: 3–20.

    Article  CAS  PubMed  Google Scholar 

  29. Hughes FM Jr, Bortner CD, Purdy GD, Cidlowski JA . Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J Biol Chem 1997; 272: 30567–30576.

    Article  CAS  PubMed  Google Scholar 

  30. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A . Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010; 7: 150–161.

    Article  CAS  PubMed  Google Scholar 

  31. Suda T, Takubo K, Semenza GL . Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 2011; 9: 298–310.

    Article  CAS  PubMed  Google Scholar 

  32. Semenza GL . Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene 2013; 32: 4057–4063.

    Article  CAS  PubMed  Google Scholar 

  33. Fiske JL, Fomin VP, Brown ML, Duncan RL, Sikes RA . Voltage-sensitive ion channels and cancer. Cancer Metastasis Rev 2006; 25: 493–500.

    Article  CAS  PubMed  Google Scholar 

  34. Urrego D, Tomczak AP, Zahed F, Stuhmer W, Pardo LA . Potassium channels in cell cycle and cell proliferation. Philos Trans R Soc London Ser B Biol Sci 2014; 369: 20130094.

    Article  Google Scholar 

  35. Cain K, Langlais C, Sun XM, Brown DG, Cohen GM . Physiological concentrations of K+ inhibit cytochrome c-dependent formation of the apoptosome. J Biol Chem 2001; 276: 41985–41990.

    Article  CAS  PubMed  Google Scholar 

  36. Karki P, Seong C, Kim JE, Hur K, Shin SY, Lee JS et al. Intracellular K(+) inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release. Cell Death Differ 2007; 14: 2068–2075.

    Article  CAS  PubMed  Google Scholar 

  37. Miller C . An overview of the potassium channel family. Genome Biol 2000; 1: REVIEWS0004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M . Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 2000; 52: 557–594.

    CAS  PubMed  Google Scholar 

  39. Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham DE et al. International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: potassium channels. Pharmacol Rev 2003; 55: 583–586.

    Article  CAS  PubMed  Google Scholar 

  40. Pardo LA, Stuhmer W . The roles of K(+) channels in cancer. Nat Rev Cancer 2014; 14: 39–48.

    Article  CAS  PubMed  Google Scholar 

  41. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138: 645–659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sachlos E, Risueno RM, Laronde S, Shapovalova Z, Lee JH, Russell J et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 2012; 149: 1284–1297.

    Article  CAS  PubMed  Google Scholar 

  43. Caouette D, Dongmo C, Berube J, Fournier D, Daleau P . Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line. Naunyn Schmiedebergs Arch Pharmacol 2003; 368: 479–486.

    Article  CAS  PubMed  Google Scholar 

  44. Wonderlin WF, Strobl JS . Potassium channels, proliferation and G1 progression. J Membr Biol 1996; 154: 91–107.

    Article  CAS  PubMed  Google Scholar 

  45. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK . Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008; 294: H570–H578.

    Article  CAS  PubMed  Google Scholar 

  46. Schumacher SM, Martens JR . Ion channel trafficking: a new therapeutic horizon for atrial fibrillation. Heart Rhythm 2010; 7: 1309–1315.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM . Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ Res 1997; 80: 772–781.

    Article  CAS  PubMed  Google Scholar 

  48. Wang Z, Fermini B, Nattel S . Delayed rectifier outward current and repolarization in human atrial myocytes. Circ Res 1993; 73: 276–285.

    Article  CAS  PubMed  Google Scholar 

  49. Platoshyn O, Brevnova EE, Burg ED, Yu Y, Remillard CV, Yuan JX . Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 2006; 290: C907–C916.

    Article  CAS  PubMed  Google Scholar 

  50. Pardo LA, Contreras-Jurado C, Zientkowska M, Alves F, Stuhmer W . Role of voltage-gated potassium channels in cancer. J Membr Biol 2005; 205: 115–124.

    Article  CAS  PubMed  Google Scholar 

  51. Bielanska J, Hernandez-Losa J, Moline T, Somoza R, Ramon y Cajal S, Condom E et al. Differential expression of Kv1.3 and Kv1.5 voltage-dependent K+ channels in human skeletal muscle sarcomas. Cancer Invest 2012; 30: 203–208.

    Article  CAS  PubMed  Google Scholar 

  52. Bielanska J, Hernandez-Losa J, Perez-Verdaguer M, Moline T, Somoza R, Ramon y Cajal S et al. Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer. Curr Cancer Drug Targets 2008; 9: 904–914.

    Article  Google Scholar 

  53. Felipe A, Bielanska J, Comes N, Vallejo A, Roig S, Ramon YCS et al. Targeting the voltage-dependent K(+) channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention. Curr Med Chem 2012; 19: 661–674.

    Article  CAS  PubMed  Google Scholar 

  54. Vallejo-Gracia A, Bielanska J, Hernandez-Losa J, Castellvi J, Ruiz-Marcellan MC, Ramon y Cajal S et al. Emerging role for the voltage-dependent K+ channel Kv1.5 in B-lymphocyte physiology: expression associated with human lymphoma malignancy. J leuk Biol 2013; 94: 779–789.

    Article  CAS  Google Scholar 

  55. Arvind S, Arivazhagan A, Santosh V, Chandramouli BA . Differential expression of a novel voltage gated potassium channel—Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma. Br J Neurosurg 2012; 26: 16–20.

    Article  CAS  PubMed  Google Scholar 

  56. Michelakis ED, Webster L, Mackey JR . Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 2008; 99: 989–994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Heshe D, Hoogestraat S, Brauckmann C, Karst U, Boos J, Lanvers-Kaminsky C . Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs. Cancer Chemother Pharmacol 2011; 67: 647–655.

    Article  CAS  PubMed  Google Scholar 

  58. Lawlor ER, Scheel C, Irving J, Sorensen PH . Anchorage-independent multi-cellular spheroids as an in vitro model of growth signaling in Ewing tumors. Oncogene 2002; 21: 307–318.

    Article  CAS  PubMed  Google Scholar 

  59. Martens JR, Navarro-Polanco R, Coppock EA, Nishiyama A, Parshley L, Grobaski TD et al. Differential targeting of Shaker-like potassium channels to lipid rafts. J Biol Chem 2000; 275: 7443–7446.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of the Lawlor and Martens labs for helpful discussion. This research was supported by grants from the CureSearch Children’s Oncology Group and Nick Currey Fund, the National Institutes of Health grants 1R01 CA134604 (to ERL), R01HL070973 (to JRM), AACR-SU2C IRG-1309 (to ERL), Pharmacological Sciences Training Program T32 GM007767 (to KER) and UM Cancer Biology Training grant 5T32 CA009676-20 (to LKS).

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

    K E Ryland & E D Vesely

  2. Department of Pediatrics and Communicable Diseases, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA

    K E Ryland, L K Svoboda & E R Lawlor

  3. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA

    J C McIntyre, L Zhang & J R Martens

  4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    E R Lawlor

Authors
  1. K E Ryland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L K Svoboda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E D Vesely
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J C McIntyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J R Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E R Lawlor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to J R Martens or E R Lawlor.

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

Ryland, K., Svoboda, L., Vesely, E. et al. Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress. Oncogene 34, 4591–4600 (2015). https://doi.org/10.1038/onc.2014.384

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.384

This article is cited by

Search

Advanced search

Quick links