DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication.
Posttranslationally modified histones and DNA hypermethylation frequently interplay to deregulate gene expression in cancer. We report that acute myeloid leukemia (AML) with an aberrant histone methyltransferase, the mixed lineage leukemia partial tandem duplication (MLL-PTD), exhibits increased global DNA methylation versus AML with MLL-wildtype (MLL-WT; P = .02). Among the differentially methylated genes, the SLC5A8 tumor suppressor gene (TSG) was more frequently hypermethylated (P = .003). In MLL-PTD(+) cell lines having SLC5A8 promoter hypermethylation, incubation with decitabine activated SLC5A8 expression. Ectopic SLC5A8 expression enhanced histones H3 and H4 acetylation in response to the histone deacetylase inhibitor, valproate, consistent with the encoded protein-SMCT1-short-chain fatty acid transport function. In addition, enhanced cell death was observed in SMCT1-expressing MLL-PTD(+) AML cells treated with valproate. Within the majority of MLL-PTD AML is a mechanism in which DNA hypermethylation silences a TSG that, together with MLL-PTD, can contribute further to aberrant chromatin remodeling and altered gene expression.
Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
Susan P
SP
Whitman
Björn
B
Hackanson
Sandya
S
Liyanarachchi
Shujun
S
Liu
Laura J
LJ
Rush
Kati
K
Maharry
Dean
D
Margeson
Ramana
R
Davuluri
Jing
J
Wen
Tatiana
T
Witte
Li
L
Yu
Chunhui
C
Liu
Clara D
CD
Bloomfield
Guido
G
Marcucci
Christoph
C
Plass
Michael A
MA
Caligiuri
D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014635:Valproic Acid / Q000494:pharmacology
D027682:Cation Transport Proteins; D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C497422:KMT2A protein, human; D027501:Monocarboxylic Acid Transporters; D009363:Neoplasm Proteins; C476760:SLC5A8 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D014635:Valproic Acid; D011495:Histone-Lysine N-Methyltransferase; D006655:Histone Deacetylases