Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells

Warren Fiskus, Yongchao Wang, Arun Sreekumar, Kathleen M. Buckley, Huidong Shi, Anand Jillella, Celalettin Ustun, Rekha Rao, Pravina Fernandez, Jianguang Chen, Ramesh Balusu, Sanjay Koul, Peter Atadja, Victor E. Marquez, Kapil N. Bhalla

Research output: Contribution to journalArticle

266 Scopus citations

Abstract

The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2, SUZ12, and EED, in which the SET (suppressor of variegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. In this study, we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) depletes EZH2 levels, and inhibits trimethylation of lysine 27 on histone H3 in the cultured human acute myeloid leukemia (AML) HL-60 and OCI-AML3 cells and in primary AML cells. DZNep treatment induced p16, p21, p27, and FBXO32 while depleting cyclin E and HOXA9 levels. Similar findings were observed after treatment with small interfering RNA to EZH2. In addition, DZNep treatment induced apoptosis in cultured and primaryAMLcells. Furthermore, compared with treatment with each agent alone, cotreatment with DZNep and the pan-histone deacetylase inhibitor panobinostat caused more depletion of EZH2, induced more apoptosis of AML, but not normal CD34+ bone marrow progenitor cells, and significantly improved survival of nonobese diabetic/ severe combined immunodeficiency mice with HL-60 leukemia. These findings indicate that the combination of DZNep and panobinostat is effective and relatively selective epigenetic therapy against AML cells.

Original languageEnglish (US)
Pages (from-to)2733-2743
Number of pages11
JournalBlood
Volume114
Issue number13
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Fiskus, W., Wang, Y., Sreekumar, A., Buckley, K. M., Shi, H., Jillella, A., Ustun, C., Rao, R., Fernandez, P., Chen, J., Balusu, R., Koul, S., Atadja, P., Marquez, V. E., & Bhalla, K. N. (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(13), 2733-2743. https://doi.org/10.1182/blood-2009-03-213496