Overexpression of human histone methylase MLL1 upon exposure to a food contaminant mycotoxin, deoxynivalenol

Khairul I Ansari; Imran Hussain; Hriday K Das; Subhrangsu S Mandal

doi:10.1111/j.1742-4658.2009.07055.x

Overexpression of human histone methylase MLL1 upon exposure to a food contaminant mycotoxin, deoxynivalenol

FEBS J. 2009 Jun;276(12):3299-307. doi: 10.1111/j.1742-4658.2009.07055.x. Epub 2009 May 5.

Authors

Khairul I Ansari¹, Imran Hussain, Hriday K Das, Subhrangsu S Mandal

Affiliation

¹ Department of Chemistry and Biochemistry, The University of Texas at Arlington, TX 76019, USA.

PMID: 19438726
DOI: 10.1111/j.1742-4658.2009.07055.x

Abstract

Mixed lineage leukemias (MLLs) are histone-methylating enzymes with critical roles in gene expression, epigenetics and cancer. Although MLLs are important gene regulators little is known about their own regulation. Herein, to understand the effects of toxic stress on MLL gene regulation, we treated human cells with a common food contaminant mycotoxin, deoxynivalenol (DON). Our results demonstrate that MLLs and Hox genes are overexpressed upon exposure to DON. Studies using specific inhibitors demonstrated that Src kinase families are involved in upstream events in DON-mediated upregulation of MLL1. Sequence analysis demonstrated that the MLL1 promoter contains multiple Sp1-binding sites and importantly, the binding of Sp1 is enriched in the MLL1 promoter upon exposure to DON. Moreover, antisense-mediated knockdown of Sp1 diminished DON-induced MLL1 upregulation. These results demonstrated that MLL1 gene expression is sensitive to toxic stress and Sp1 plays crucial roles in the stress-induced upregulation of MLL1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites / genetics
Blotting, Western
Cell Line, Tumor
Chromatin Immunoprecipitation
Dose-Response Relationship, Drug
Gene Expression Regulation, Neoplastic / drug effects*
Histone-Lysine N-Methyltransferase
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Myeloid-Lymphoid Leukemia Protein / genetics*
Myeloid-Lymphoid Leukemia Protein / metabolism
Oligonucleotides, Antisense / genetics
Promoter Regions, Genetic / genetics
Protein Binding / drug effects
Pyrimidines / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Sp2 Transcription Factor / genetics
Sp2 Transcription Factor / metabolism
Transfection
Trichothecenes / pharmacology*
src-Family Kinases / antagonists & inhibitors
src-Family Kinases / metabolism

Substances

AG 1879
HOXA7 protein, human
Homeodomain Proteins
KMT2A protein, human
Oligonucleotides, Antisense
Pyrimidines
Trichothecenes
Sp2 Transcription Factor
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
src-Family Kinases
deoxynivalenol