C20orf20 (MRG-binding protein) as a potential therapeutic target for colorectal cancer

Colorectal cancer is the second leading cause of cancer death in the United States, and its incidence rates are increasing in Japan. It is estimated that there are almost 500 000 colorectal cancer-related deaths every year in the world (Parkin, 2001). Although recent medical advances have improved the prognosis of patients with the disease, complete cure of patients with advanced tumour is far from satisfactory. In chemotherapies for advanced colorectal cancer, oxaliplatin/fluorouracil/leucovorin (FOLFOX) is an effective and well-tolerated regimen. Combination of targeted biological agents such as anti-epidermal growth factor receptor (EGFR) with FOLFOX have been reported to enhance the efficacy against EGFR-expressing metastatic colorectal cancer (Giantonio, 2006; Tabernero et al, 2007). This indicates that the use of rationally selected therapeutic agents will improve the treatment for advanced diseases and results in increase of cure rate and/or prolonged survival. Regarding colorectal cancer, combination chemotherapy with Bevacizumab, an inhibitor of VEGF receptor, was approved in the United States and was shown to be effective for 45% of patients with colorectal cancer and increased their 1-year survival rate from 63.4% to 74.3% (Hurwitz et al, 2004). However, many patients are still suffering and dying from the disease, and development of additional molecular-targeted anti-cancer drugs is a matter of pressing concern for public health. These drugs target molecules that are expressed abundantly or exclusively in cancer cells and functioning as an indispensable factor for the growth or survival of cancer cells. For instance, Imatinib (STI571) inhibits several protein kinases such as bcr-abl fusion protein in chronic myelogenous leukaemia, and c-kit in gastrointestinal stromal tumours (O'Dwyer and Druker, 2000). Gefetinib targets the ATP cleft within the EGFR (Wakeling, 2002; Fukuoka et al, 2003; Gridelli et al, 2003; Kris et al, 2003). Trastuzumab is a monoclonal antibody to the HER2/neu receptor, which is overexpressed in ∼30% of breast cancers (Molina et al, 2001). These drugs strikingly suppressed the growth of tumour cells and showed minimum cytotoxic effect in normal cells. Therefore, for the development of molecular-targeted anti-cancer drugs pinpointing cancer cells, identification of molecules that are expressed abundantly in cancer cells and clarification of their function are essential. Molecular studies have clarified that multiple-step process has an important function in colorectal carcinogenesis, which involves activation of oncogenes such as K-ras, and inactivation of tumour suppressor genes such as p53 and APC. In addition to these genetic changes, alteration of gene expression is involved in the carcinogenesis. Epigenetic alterations including aberrant DNA methylation and/or histone modification have been recently shown to participate in some of the deregulated gene expression. To unveil the molecular mechanisms of colorectal cancer and discover target molecules for the development of novel anti-cancer drugs, we analysed global gene-expression profiles of colorectal tumours by cDNA microarray analysis representing 23 040 genes (Lin et al, 2002). These efforts have identified a number of genes, which are frequently either up-regulated or down-regulated in the tumours compared with the corresponding non-cancerous tissues. Among the list of genes up-regulated in the tumours, we found a gene termed as MRG-binding protein (MRGBP), with an approved symbol of chromosome 20 open reading frame 20 (C20orf20), which was identified as a component of TRRAP/TIP60 histone acetyltransferase complex and shown to bind directly to MRG15 and MRGX proteins (Cai et al, 2003). In this report, we show, for the first time, that MRGBP expression was frequently elevated in colorectal cancer, and that it has an important function in the growth of cancer cells. These findings should contribute to a better understanding of colorectal tumourigenesis, and may serve as a starting point for the development of novel strategies for prevention and treatment of colorectal cancer.