Skip to main content
Log in

Emodin can induce K562 cells to erythroid differentiation and improve the expression of globin genes

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

In China, the traditional Chinese medicine “YiSui ShenXu Granule” has been used for treating β-thalassemia over 20 years and known to be effective in clinic. Several purified components from “YiSui ShenXu Granule” are tested in K562 cells to reveal its effect on globin expression and erythroid differentiation, and one of the purified components, emodin, was demonstrated to increase the expression of α-, ε-, γ-globin, CD235a, and CD71 in K562 cells. Moreover, the increase of their expression is emodin concentration-dependent. The mRNA and microRNA (miRNA) expression profiles are further analyzed and 417 mRNAs and 35 miRNAs with differential expression between untreated and emodin-treated K562 cells were identified. Among them, two mRNAs that encode known positive regulators of erythropoiesis, ALAS2, and c-KIT respectively, increased during emodin-induced K562 erythroid differentiation, meanwhile, two negative regulators, miR-221 and miR-222, decreased during this process. These results indicate that emodin can improve the expression of globin genes in K562 cells and also induce K562 cells to erythroid differentiation possibly through up-regulating ALAS2 and c-KIT and down-regulating miR-221 and miR-222.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ley TJ, DeSimone J, Anagnou NP, Keller GH, Humphries RK, Turner PH, Young NS, Keller P, Nienhuis AW (1982) 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta + thalassemia. N Engl J Med 307:1469–1475

    Article  PubMed  CAS  Google Scholar 

  2. Nienhuis AW, Ley TJ, Humphries RK, Young NS, Dover G (1985) Pharmacological manipulation of fetal hemoglobin synthesis in patients with severe beta-thalassemia. Ann N Y Acad Sci 445:198–211

    Article  PubMed  CAS  Google Scholar 

  3. Liu DP, Liang CC, Ao ZH, Jia PC, Chen SS, Wang RX, Liu LJ, Jin HQ, Zha DY, Huang YW (1990) Treatment of severe beta-thalassemia (patients) with myleran. Am J Hematol 33:50–55

    Article  PubMed  CAS  Google Scholar 

  4. Perrine SP, Miller BA, Faller DV, Cohen RA, Vichinsky EP, Hurst D, Lubin BH, Papayannopoulou T (1989) Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia. Blood 74:454–459

    PubMed  CAS  Google Scholar 

  5. Chalevelakis G, Yalouris AG, Lyberatos C, Economopoulos T, Anastasiou C, Hatziioannou J, Raptis S (1989) Effect of isoniazid, a haem inhibitor, on globin chain synthesis in reticulocytes from non-thalassaemic and beta thalassaemic subjects. J Clin Pathol 42:977–981

    Article  PubMed  CAS  Google Scholar 

  6. Wu ZK, Zhang XH, Li M (2006) Clinical observation on effects of Yisui Shengxue Granule in treating 156 patients with beta-thalassemia. Zhongguo Zhong Xi Yi Jie He Za Zhi 26:352–354

    PubMed  Google Scholar 

  7. Zhang L, Lau YK, Xi L, Hong RL, Kim DS, Chen CF, Hortobagyi GN, Chang C, Hung MC (1998) Tyrosine kinase inhibitors, emodin and its derivative repress HER-2/neu-induced cellular transformation and metastasis-associated properties. Oncogene 16:2855–2863

    Article  PubMed  CAS  Google Scholar 

  8. Pecere T, Gazzola MV, Mucignat C, Parolin C, Vecchia FD, Cavaggioni A, Basso G, Diaspro A, Salvato B, Carli M, Palù G (2000) Aloe-emodin is a new type of anticancer agent with selective activity against neuroectodermal tumors. Cancer Res 60:2800–2804

    PubMed  CAS  Google Scholar 

  9. Feng Y, Huang SL, Dou W, Zhang S, Chen JH, Shen Y, Shen JH, Leng Y (2010) Emodin, a natural product, selectively inhibits 11beta-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice. Br J Pharmacol 161:113–126

    Article  PubMed  CAS  Google Scholar 

  10. Bakker WJ, Blázquez-Domingo M, Kolbus A, Besooyen J, Steinlein P, Beug H, Coffer PJ, Löwenberg B, von Lindern M, van Dijk TB (2004) FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1. J Cell Biol 164:175–184

    Article  PubMed  CAS  Google Scholar 

  11. Marinkovic D, Zhang X, Yalcin S, Luciano JP, Brugnara C, Huber T, Ghaffari S (2007) Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 117:2133–2144

    Article  PubMed  CAS  Google Scholar 

  12. Filipe A, Li Q, Deveaux S, Godin I, Romeo PH, Stamatoyannopoulos G, Mignotte V (1999) Regulation of embryonic/fetal globin genes by nuclear hormone receptors: a novel perspective on hemoglobin switching. EMBO J 18:687–697

    Article  PubMed  CAS  Google Scholar 

  13. Wang D, Li Y, Shen B (2002) A novel erythroid differentiation related gene EDRF1 upregulating globin gene expression in HEL cells. Chin Med J (Engl) 115:1701–1705

    CAS  Google Scholar 

  14. Zhang FL, Shen GM, Liu XL, Wang F, Zhao HL, Yu J, Zhang JW (2011) Hypoxic induction of human erythroid-specific δ-aminolevulinate synthase mediated by hypoxia-inducible factor 1. Biochemistry 50:1194–1202

    Article  PubMed  CAS  Google Scholar 

  15. Kawano T, Horiguchi-Yamada J, Saito S, Iwase S, Furukawa Y, Kano Y, Yamada H (2004) Ectopic cyclin D1 expression blocks STI571-induced erythroid differentiation of K562 cells. Leuk Res 28:623–629

    Article  PubMed  CAS  Google Scholar 

  16. Duff C, Smith-Miles K, Lopes L, Tian T (2012) Mathematical modelling of stem cell differentiation: the PU.1-GATA-1 interaction. J Math Biol 64:449–468

    Article  PubMed  Google Scholar 

  17. Fernández-Nestosa MJ, Hernández P, Schvartzman JB, Krimer DB (2008) PU.1 is dispensable to block erythroid differentiation in Friend erythroleukemia cells. Leuk Res 32:121–130

    Article  PubMed  Google Scholar 

  18. Lorsbach RB, Moore J, Ang SO, Sun W, Lenny N, Downing JR (2004) Role of RUNX1 in adult hematopoiesis: analysis of RUNX1-IRES-GFP knock-in mice reveals differential lineage expression. Blood 103:2522–2529

    Article  PubMed  CAS  Google Scholar 

  19. Yokomizo T, Hasegawa K, Ishitobi H, Osato M, Ema M, Ito Y, Yamamoto M, Takahashi S (2008) Runx1 is involved in primitive erythropoiesis in the mouse. Blood 111:4075–4080

    Article  PubMed  CAS  Google Scholar 

  20. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  21. Borel C, Deutsch S, Letourneau A, Migliavacca E, Montgomery SB, Dimas AS, Vejnar CE, Attar H, Gagnebin M, Gehrig C, Falconnet E, Dupré Y, Dermitzakis ET, Antonarakis SE (2011) Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts. Genome Res 21:68–73

    Article  PubMed  CAS  Google Scholar 

  22. Macfarlane LA, Murphy PR (2010) MicroRNA: biogenesis, Function and Role in Cancer. Curr Genomics 11:537–561

    Article  PubMed  CAS  Google Scholar 

  23. Zhan M, Miller CP, Papayannopoulou T, Stamatoyannopoulos G, Song CZ (2007) MicroRNA expression dynamics during murine and human erythroid differentiation. Exp Hematol 35:1015–1025

    Article  PubMed  CAS  Google Scholar 

  24. Sankaran VG, Menne TF, Šćepanović D, Vergilio JA, Ji P, Kim J, Thiru P, Orkin SH, Lander ES, Lodish HF (2011) MicroRNA-15a and -16–1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proc Natl Acad Sci USA 108:1519–1524

    Article  PubMed  CAS  Google Scholar 

  25. Gabbianelli M, Testa U, Morsilli O, Pelosi E, Saulle E, Petrucci E, Castelli G, Giovinazzi S, Mariani G, Fiori ME, Bonanno G, Massa A, Croce CM, Fontana L, Peschle C (2010) Mechanism of human Hb switching: a possible role of the kit receptor/miR 221–222 complex. Haematologica 95:1253–1260

    Article  PubMed  CAS  Google Scholar 

  26. Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C (2005) MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 102:18081–18086

    Article  PubMed  CAS  Google Scholar 

  27. Lu L, Dai MS, Ge Y, Wang LS, Braun SE, Wait CL, Griffith DJ, Heinrich MC, Broxmeyer HE (2000) Co-transduction of cDNAs for c-kit and steel factor into single CD34+ cord blood cells further enhances the growth of erythroid and multipotential progenitors. J Hematother Stem Cell Res 9:813–825

    Article  PubMed  CAS  Google Scholar 

  28. Dai MS, Heinrich MC, Broxmeyer HE, Lu L (2000) Enhancing effects of co-transduction of both human erythropoietin receptor and c-kit cDNAs into hematopoietic stem/progenitor cells from cord blood on proliferation and differentiation of erythroid progenitors. Cytokines Cell Mol Ther 6:1–8

    Article  PubMed  CAS  Google Scholar 

  29. Kucerova J, Horvathova M, Mojzikova R, Belohlavkova P, Cermak J, Divoky V (2011) New mutation in erythroid-specific delta-aminolevulinate synthase as the cause of X-linked sideroblastic anemia responsive to pyridoxine. Acta Haematol 125:193–197

    Article  PubMed  Google Scholar 

  30. Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli-Vergani G, Deybach JC, Puy H (2008) C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 83:408–414

    Article  PubMed  CAS  Google Scholar 

  31. Liu YM, Wu ZK, Chai LM, Zhang XH, Li M, Chen YY, Lv XX, Zhu XY (2007) Effect on expression of mice alpha-hemoglobin stabilizing protein in different developmental stages treated with Yisui Shengxue granules. Zhongguo Zhong Yao Za Zhi 32:609–612

    PubMed  Google Scholar 

  32. Zhang C, Wu ZK (2008) Molecular pharmacological basis of the YiSui ShenXu Granule in beta-thalassemia therapy. J Ethnopharmacol 120:437–441

    Article  PubMed  CAS  Google Scholar 

  33. Kramer MF, Gunaratne P, Ferreira GC (2000) Transcriptional regulation of the murine erythroid-specific 5-aminolevulinate synthase gene. Gene 247:153–166

    Article  PubMed  CAS  Google Scholar 

  34. Tripic T, Deng W, Cheng Y, Zhang Y, Vakoc CR, Gregory GD, Hardison RC, Blobel GA (2009) SCL and associated proteins distinguish active from repressive GATA transcription factor complexes. Blood 113:2191–2201

    Article  PubMed  CAS  Google Scholar 

  35. Kaneko H, Shimizu R, Yamamoto M (2010) GATA factor switching during erythroid differentiation. Curr Opin Hematol 17:163–168

    Article  PubMed  CAS  Google Scholar 

  36. Liberati C, Cera MR, Secco P, Santoro C, Mantovani R, Ottolenghi S, Ronchi A (2001) Cooperation and competition between the binding of COUP-TFII and NF-Y on human epsilon- and gamma-globin gene promoters. J Biol Chem 276:41700–41709

    Article  PubMed  CAS  Google Scholar 

  37. Aerbajinai W, Zhu J, Kumkhaek C, Chin K, Rodgers GP (2009) SCF induces gamma-globin gene expression by regulating downstream transcription factor COUP-TFII. Blood 114:187–194

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Basic Research Program of China (2010CB530406) and the National Natural Science Foundation of China (31201103).

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jun-Wu Zhang.

Additional information

Yan-Ni Ma and Ming-Tai Chen contributed to this work equally.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, YN., Chen, MT., Wu, ZK. et al. Emodin can induce K562 cells to erythroid differentiation and improve the expression of globin genes. Mol Cell Biochem 382, 127–136 (2013). https://doi.org/10.1007/s11010-013-1726-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1726-3

Keywords

Navigation