Skip to main content
SpringerLink
Log in

Growth Inhibition Accompanied by MOB1 Upregulation in Human Acute Lymphoid Leukemia Cells by 3-Deazaneplanocin A

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

Our purpose was to investigate the effect of 3-deazaneplanocin A (DZNep) on human T-cell acute lymphoid leukemia (T-ALL) cells, and to explore the underlying molecular mechanisms. The human T-ALL cell line Molt4 was treated with DZNep, and cell proliferation was examined. The expression of Mps one binder kinase activator 1 gene (MOB1) mRNA and protein was determined by RT-PCR and Western blotting, respectively. The histone modification effect of DZNep on the lysine 9 of histone 3 associated with MOB1 promoters was examined with chromatin immunoprecipitation and quantitative PCR, and CpG methylation in MOB1 promoters was detected by bisulfite sequencing PCR. DZNep treatment inhibited the growth of Molt4 cells. The expressions of MOB1 genes were upregulated by DZNep treatment, and histone methylations in their promoters were significantly reduced. The results indicate that DZNep is a promising therapeutic compound for the treatment of human T-ALL.

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

Similar content being viewed by others

References

  • Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174

    Article  CAS  PubMed  Google Scholar 

  • Belson M, Kingsley B, Holmes A (2007) Risk factors for acute leukemia in children: a review. Environ Health Perspect 115:138–145

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chan SW, Lim CJ, Chen L et al (2011) The Hippo pathway in biological control and cancer development. J Cell Physiol 226:928–939

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Li J, Han Q et al (2012) Enhancer of zeste homolog 2 is overexpressed and contributes to epigenetic inactivation of p21 and phosphatase and tensin homolog in B-cell acute lymphoblastic leukemia. Exp Biol Med 237:1110–1116

    Article  CAS  Google Scholar 

  • Chow A, Hao Y, Yang X (2010) Molecular characterization of human homologs of yeast MOB1. Int J Cancer 126:2079–2089

    CAS  PubMed  Google Scholar 

  • Fiskus W, Wang Y, Sreekumar A et al (2009) Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114:2733–2743

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Florindo C, Perdigao J, Fesquet D, Schiebel E, Pines J, Tavares AA (2012) Human Mob1 proteins are required for cytokinesis by controlling microtubule stability. J Cell Sci 125:3085–3090

    Article  CAS  PubMed  Google Scholar 

  • Girard N, Bazille C, Lhuissier E et al (2014) 3-Deazaneplanocin A (DZNep), an inhibitor of the histone methyltransferase EZH2, induces apoptosis and reduces cell migration in chondrosarcoma cells. Plos One 9:e98176

    Article  PubMed Central  PubMed  Google Scholar 

  • Gokbuget N, Hoelzer D (2009) Treatment of adult acute lymphoblastic leukemia. Semin Hematol 46:64–75

    Article  PubMed  Google Scholar 

  • Hao Y, Chun A, Cheung K, Rashidi B, Yang X (2008) Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 283:5496–5509

    Article  CAS  PubMed  Google Scholar 

  • Hergovich A (2011) MOB control: reviewing a conserved family of kinase regulators. Cell Signal 23:1433–1440

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Herman JG, Baylin I (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054

    Article  CAS  PubMed  Google Scholar 

  • Ho LL, Wei X, Shimizu T, Lai ZC (2010) Mob as tumor suppressor is activated at the cell membrane to control tissue growth and organ size in Drosophila. Dev Biol 337:274–283

    Article  CAS  PubMed  Google Scholar 

  • Jaffe JD, Wang Y, Chan HM et al (2013) Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat Genet 45:1386–1391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kuo AJ, Cheung P, Chen K et al (2011) NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell 44:609–620

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lai ZC, Wei X, Shimizu T et al (2005) Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120:675–685

    Article  CAS  PubMed  Google Scholar 

  • Lee JK, Kim KC (2013) DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells. Biochem Biophys Res Commun 438:647–652

    Article  CAS  PubMed  Google Scholar 

  • Lignitto L, Arcella A, Sepe M et al (2013) Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth. Nat Commun 4:1822

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu AM, Wong KF, Jiang X, Qiao Y, Luk JM (2012) Regulators of mammalian Hippo pathway in cancer. Biochim Biophys Acta 1826:357–364

    CAS  PubMed  Google Scholar 

  • Luo X (2010) Snapshots of a hybrid transcription factor in the Hippo pathway. Protein Cell 1:811–819

    Article  CAS  PubMed  Google Scholar 

  • Miranda TB, Cortez CC, Yoo CB et al (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 8:1579–1588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moorman AV (2012) The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia. Blood Rev 26:123–135

    Article  CAS  PubMed  Google Scholar 

  • Praskova M, Xia F, Avruch J (2008) MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol 18:311–321

    Article  CAS  PubMed  Google Scholar 

  • Sasaki H, Kawano O, Endo K et al (2007) Human MOB1 expression in non-small-cell lung cancer. Clin Lung Cancer 8:273–276

    Article  CAS  PubMed  Google Scholar 

  • Shimizu T, Ho LL, Lai ZC (2008) The mob as tumor suppressor gene is essential for early development and regulates tissue growth in Drosophila. Genetics 178:957–965

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tan J, Yang X, Zhuang L et al (2007) Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Gene Dev 21:1050–1063

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tavares A, Goncalves J, Florindo C, Tavares AA, Soares H (2012) Mob1: defining cell polarity for proper cell division. J Cell Sci 125:516–527

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Zang C, Rosenfeld JA et al (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40:897–903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wei X, Shimizu T, Lai ZC (2007) Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J 26:1772–1781

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zeng Q, Hong W (2008) The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell 13:188–192

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, George J, Deb S et al (2011) The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 30:2810–2822

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Bi C, Cheong LL et al (2011) The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood 118:2830–2839

    Article  PubMed  Google Scholar 

  • Zhou Y, You MJ, Young KH et al (2012) Advances in the molecular pathobiology of B-lymphoblastic leukemia. Hum Pathol 43:1347–1362

    Article  CAS  PubMed  Google Scholar 

  • Zhu WG, Srinivasan K, Dai Z et al (2003) Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol Cell Biol 23:4056–4065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zou Y, Ma X, Huang Y, Hong L, Chiao JW (2012) Effect of phenylhexyl isothiocyanate on aberrant histone H3 methylation in primary human acute leukemia. J Hematol Oncol 5:36–42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Fujian Institute of Hematology, Union Hospital of Fujian Medical University, Fuzhou, 35001, Fujian, People’s Republic of China

    Jianzhen Shen, Junnan Su, Dansen Wu, Feng Zhang, Haiying Fu, Huarong Zhou & Meihong Xu

  2. Fujian Institute of Hematology, Union Hospital, Fujian Medical University, Fuzhou, 350001, Fujian, People’s Republic of China

    Jianzhen Shen

Authors
  1. Jianzhen Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junnan Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dansen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haiying Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huarong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Meihong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianzhen Shen.

Ethics declarations

Declaration of interest

The authors report no declarations of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, J., Su, J., Wu, D. et al. Growth Inhibition Accompanied by MOB1 Upregulation in Human Acute Lymphoid Leukemia Cells by 3-Deazaneplanocin A. Biochem Genet 53, 268–279 (2015). https://doi.org/10.1007/s10528-015-9688-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-015-9688-7

Keywords

Search

Navigation