Document Detail


Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex.
MedLine Citation:
PMID:  23287862     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
An exciting recent approach to targeting transcription factors in cancer is to block formation of oncogenic complexes. We investigated whether interfering with the interaction of the transcription factor SALL4, which is critical for leukemic cell survival, and its epigenetic partner complex represents a novel therapeutic approach. The mechanism of SALL4 in promoting leukemogenesis is at least in part mediated by its repression of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through its interaction with a histone deacetylase (HDAC) complex. In this study, we demonstrate that a peptide can compete with SALL4 in interacting with the HDAC complex and reverse its effect on PTEN repression. Treating SALL4-expressing malignant cells with this peptide leads to cell death that can be rescued by a PTEN inhibitor. The antileukemic effect of this peptide can be confirmed on primary human leukemia cells in culture and in vivo, and is identical to that of down-regulation of SALL4 in these cells using an RNAi approach. In summary, our results demonstrate a novel peptide that can block the specific interaction between SALL4 and its epigenetic HDAC complex in regulating its target gene, PTEN. Furthermore, targeting SALL4 with this approach could be an innovative approach in treating leukemia.
Authors:
Chong Gao; Todor Dimitrov; Kol Jia Yong; Hiro Tatetsu; Ha-won Jeong; Hongbo R Luo; James E Bradner; Daniel G Tenen; Li Chai
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-03
Journal Detail:
Title:  Blood     Volume:  121     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-22     Completed Date:  2013-04-24     Revised Date:  2014-02-23    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1413-21     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Carcinoma, Hepatocellular
Drug Design
Endometrial Neoplasms
Epigenesis, Genetic / drug effects*,  genetics
Female
Gene Expression Regulation, Leukemic / drug effects*,  physiology
HL-60 Cells
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / pharmacology
Humans
Hydroxamic Acids / pharmacology
Leukemia, Monocytic, Acute
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Acute* / drug therapy,  genetics,  mortality
Liver Neoplasms
Male
Mice
Mice, Inbred NOD
Mice, SCID
PTEN Phosphohydrolase / genetics,  metabolism
Peptide Fragments / pharmacology
Proto-Oncogene Proteins c-akt / metabolism
Transcription Factors / antagonists & inhibitors*,  genetics,  metabolism
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
P01 DK080665/DK/NIDDK NIH HHS; P01 DK080665/DK/NIDDK NIH HHS; P01 HL095489/HL/NHLBI NIH HHS; P01HL095489/HL/NHLBI NIH HHS; R01 HL092437/HL/NHLBI NIH HHS; R01HL092437/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Peptide Fragments; 0/SALL4 protein, human; 0/Transcription Factors; 3X2S926L3Z/trichostatin A; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; EC 3.5.1.98/HDAC1 protein, human; EC 3.5.1.98/HDAC2 protein, human; EC 3.5.1.98/Histone Deacetylase 1; EC 3.5.1.98/Histone Deacetylase 2
Comments/Corrections

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