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Downregulation of HO-1 promoted apoptosis induced by decitabine via increasing p15INK4B promoter demethylation in myelodysplastic syndrome

Gene Therapy volume 22, pages 287–296 (2015)Cite this article

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Abstract

Decitabine, which reverses hypermethylation of the p15INK4B gene in vitro, has been used to relieve cytopenias and blast excess in over 50% of patients with high-risk myelodysplastic syndrome (MDS). In this study, heme oxygenase-1 (HO-1) was overexpressed in MDS cell line SKM-1, which was closely related to resistance to decitabine-induced apoptosis. We aimed to further investigate the role of HO-1 in apoptosis induced by low-dose decitabine in SKM-1 cells. Upregulation of HO-1 by transfecting it into SKM-1 cells with lentivirus vector promoted cell proliferation and protected them against apoptosis. In contrast, downregulation of HO-1 enhanced decitabine-induced apoptosis but reduced accumulation of the S phase in cell cycle. To explore the mechanism, the expressions of cell cycle-related proteins were detected after the cells were treated by decitabine in each group. p15INK4B and CDK4 were overexpressed in SKM-1 cells in which HO-1 was inhibited, and the expression-depending apoptosis was related to the caspase-3 pathway. Even though HO-1 was silenced, the apoptotic rate never increased as the caspase-3 pathway was blocked. It is well known that p15INK4B dominantly regulates the S phase of the cell cycle. p15INK4B was herein demethylated more evidently in the group of SKM-1 cells in which HO-1 was downregulated, as well as in the mononuclear cells of patients suffering from MDS. In the case of poor prognosis, the mRNA level of HO-1 was raised. In conclusion, overexpression of HO-1 indicated resistance to demethylation of p15INK4B induced by decitabine.

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Acknowledgements

This work was supported, in part, by the National Natural Science foundation of China (No. 81070444, 81270636, 81360501 and 81470006), International cooperation project of GuiZhou Province (No. 2011-7010), Social project of GuiZhou Province (No. 2011-3012), Provincial governor special fund of GuiZhou Province (No. 2010-84), and Project of Science and Technology Bureau of Guiyang City (No. 2012103-36).

Author Contributions

MD, WP, GR and SJ performed research; MD, LY and FQ analyzed data; MD and WJ wrote the paper; and MD designed experiments.

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Author notes

  1. D Ma and Q Fang: Dan Ma and Qin Fang are co-first authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China

    D Ma, P Wang, R Gao, Y Li, X Y Hu & J S Wang

  2. Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China

    D Ma, P Wang, R Gao, Y Li, X Y Hu & J S Wang

  3. GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China

    D Ma, P Wang, R Gao, Y Li, X Y Hu & J S Wang

  4. Department of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical College, China

    D Ma & Q Fang

  5. Department of Pharmacy, Affiliated Hospital of Guiyang Medical College, Guiyang, China

    Q Fang

  6. School of Pharmacy, Guiyang Medical College, Guiyang, China

    J Sun

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Correspondence to J S Wang.

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Ma, D., Fang, Q., Wang, P. et al. Downregulation of HO-1 promoted apoptosis induced by decitabine via increasing p15INK4B promoter demethylation in myelodysplastic syndrome. Gene Ther 22, 287–296 (2015). https://doi.org/10.1038/gt.2015.1

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