Overexpression of cohesion establishment factor DSCC1 through E2F in colorectal cancer.
Ctf18-replication factor C complex including Dscc1 (DNA replication and sister chromatid cohesion 1) is implicated in sister chromatid cohesion, DNA replication, and genome stability in S. cerevisiae and C. elegans. We previously performed gene expression profiling in primary colorectal cancer cells in order to identify novel molecular targets for the treatment of colorectal cancer. A feature of the cancer-associated transcriptional signature revealed from this effort is the elevated expression of the proto-oncogene DSCC1. Here, we have interrogated the molecular basis for deviant expression of human DSCC1 in colorectal cancer and its ability to promote survival of cancer cells. Quantitative PCR and immunohistochemical analyses corroborated that the expression level of DSCC1 is elevated in 60-70% of colorectal tumors compared to their matched noncancerous colonic mucosa. An in silico evaluation of the presumptive DSCC1 promoter region for consensus DNA transcriptional regulatory elements revealed a potential role for the E2F family of DNA-binding proteins in controlling DSCC1 expression. RNAi-mediated reduction of E2F1 reduced expression of DSCC1 in colorectal cancer cells. Gain- and loss-of-function experiments demonstrated that DSCC1 is involved in the viability of cancer cells in response to genotoxic stimuli. We reveal that E2F-dependent expression of DSCC1 confers anti-apoptotic properties in colorectal cancer cells, and that its suppression may be a useful option for the treatment of colorectal cancer.
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kiyoshi
K
Yamaguchi
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Rui
R
Yamaguchi
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Norihiko
N
Takahashi
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tsuneo
T
Ikenoue
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tomoaki
T
Fujii
Department of Surgery, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Masaru
M
Shinozaki
Department of Surgery, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Giichiro
G
Tsurita
Department of Surgery, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Keisuke
K
Hata
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Atsushi
A
Niida
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Seiya
S
Imoto
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan ; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Satoru
S
Miyano
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yusuke
Y
Nakamura
Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yoichi
Y
Furukawa
D017209:Apoptosis; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D000090063:Proto-Oncogene Mas
D002352:Carrier Proteins; C477292:DSCC1 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D016203:CDC2 Protein Kinase