ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression

作者：Kumamoto Kensuke; Fujita Kaori; Kurotani Reiko; Saito Motonobu; Unoki Motoko; Hagiwara Nobutoshi; Shiga Hideaki; Bowman Elise D; Yanaihara Nozomu; Okamura Shu; Nagashima Makoto; Miyamoto Kotaro; Takenoshita Seiichi; Yokota Jun; Harris Curtis C^*

来源：International Journal of Cancer, 2009, 125(6): 1306-1315.

DOI：10.1002/ijc.24437

• ING2
• MMP13
• chromatin remodeling
• colon cancer
• metastasis
• NF-kappa B

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-kappa B binding site was found in the ING2 promoter region. We confirmed that NF-kappa B 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. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America.

• 出版日期2009-9-15