title: Downregulation of HO-1 promoted apoptosis induced by decitabine via increasing p15INK4B promoter demethylation in myelodysplastic syndrome.
abstract: Decitabine, which reverses hypermethylation of the p15(INK4B) 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. p15(INK4B) 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 p15(INK4B) dominantly regulates the S phase of the cell cycle. p15(INK4B) 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 p15(INK4B) induced by decitabine.
authors: 1] Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China [2] Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China [3] GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China [4] Department of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical College, China.
authors: D
authors: D
authors: Ma
authors: 1] Department of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical College, China [2] Department of Pharmacy, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
authors: Q
authors: Q
authors: Fang
authors: 1] Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China [2] Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China [3] GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
authors: P
authors: P
authors: Wang
authors: 1] Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China [2] Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China [3] GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
authors: R
authors: R
authors: Gao
authors: School of Pharmacy, Guiyang Medical College, Guiyang, China.
authors: J
authors: J
authors: Sun
authors: 1] Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China [2] Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China [3] GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
authors: Y
authors: Y
authors: Li
authors: 1] Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China [2] Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China [3] GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
authors: X Y
authors: XY
authors: Hu
authors: 1] Department of Hematology, Affiliated Hospital of Guiyang Medical College, Guiyang, China [2] Key Laboratory of Hematological Disease Diagnostic, Treat Centre of GuiZhou Province, Guiyang, China [3] GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College, Guiyang, China.
authors: J S
authors: JS
authors: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism*; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D059807:S Phase Cell Cycle Checkpoints; D055815:Young Adult
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D004791:Enzyme Inhibitors; D000077209:Decitabine; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D001374:Azacitidine
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