Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism.
Cdc42, a member of Rho GTPases family, is involved in the regulation of several cellular functions, such as rearrangement of actin cytoskeleton, membrane trafficking, cell-cycle progression, and transcriptional regulation. Aberrant expression or activity of Cdc42 has been reported in several tumours. Here, the specific role of Cdc42 in development and progression of colorectal cancer was analyzed through microarrays technology. A comparative analysis of Cdc42 overexpressing cells versus cells with decreased Cdc42 levels through siRNA revealed that Cdc42 overexpression down-regulated the potential tumour suppressor gene ID4. Results were validated by quantitative RT-PCR and the methylation status of the specific promoter, analyzed. Methylation-specific PCR and bisulfite sequencing PCR analysis revealed that Cdc42 induced the methylation of the CpG island of the ID4 promoter. Colorectal adenocarcinoma samples were compared with the corresponding adjacent normal tissue of the same patient in order to determine specific gene expression levels. The downregulation of ID4 by Cdc42 was also found of relevance in colorectal adenocarcinoma biopsies. Cdc42 was found to be overexpressed with high incidence (60%) in colorectal cancer samples, and this expression was associated with silencing of ID4 with statistical significance (p<0.05). Cdc42 may have a role in the development of colon cancer. Furthermore, inhibition of Cdc42 activity may have a direct impact in the management of colorectal cancer.
Centro Nacional de Biotecnología, Madrid, Spain.
Teresa
T
Gómez Del Pulgar
Fátima
F
Valdés-Mora
Eva
E
Bandrés
Rosa
R
Pérez-Palacios
Carolina
C
Espina
Paloma
P
Cejas
Miguel Angel
MA
García-Cabezas
Manuel
M
Nistal
Enrique
E
Casado
Manuel
M
González-Barón
Jesús
J
García-Foncillas
Juan Carlos
JC
Lacal
D000230:Adenocarcinoma / Q000737:chemistry* / Q000628:therapy; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000209:etiology / Q000628:therapy; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D020764:cdc42 GTP-Binding Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D020764:cdc42 GTP-Binding Protein