ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression.
Inhibitor of growth 2 (ING2) is associated with chromatin remodeling and regulation of gene expression by binding to a methylated histone H3K4 residue and recruiting HDAC complexes to the region. The aim of our study is to investigate the regulation of ING2 expression and the clinical significance of upregulated ING2 in colon cancer. Here, we show that the ING2 mRNA level in colon cancer tissue increased to more than twice than that in normal mucosa in the 45% of colorectal cancer cases that we examined. A putative NF-kappaB binding site was found in the ING2 promoter region. We confirmed that NF-kappaB could bind to the ING2 promoter by EMSA and luciferase assays. Subsequent microarray analyses revealed that ING2 upregulates expression of matrix metalloproteinase 13 (MMP13), which enhances cancer invasion and metastasis. ING2 regulation of MMP13 expression was confirmed in both ING2 overexpression and knock down experiments. MMP13 expression was further induced by coexpression of ING2 with HDAC1 or with mSin3A, suggesting that the ING2-HDAC1-mSin3A complex members regulates expression of MMP13. In vitro invasion assay was performed to determine functional significance of ING2 upregulation. ING2 overexpressed cells exhibited greater invasive potential. Taken together, upregulation of ING2 was associated with colon cancer and MMP13-dependent cellular invasion, indicating that ING2 expression might be involved with cancer invasion and metastasis.
Kumamoto
Kensuke
K
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA.
Fujita
Kaori
K
Kurotani
Reiko
R
Saito
Motonobu
M
Unoki
Motoko
M
Hagiwara
Nobutoshi
N
Shiga
Hideaki
H
Bowman
Elise D
ED
Yanaihara
Nozomu
N
Okamura
Shu
S
Nagashima
Makoto
M
Miyamoto
Kotaro
K
Takenoshita
Seiichi
S
Yokota
Jun
J
Harris
Curtis C
CC
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C444654:ING2 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D025521:Tumor Suppressor Proteins; D008156:Luciferases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex