The Cables gene on chromosome 18q is silenced by promoter hypermethylation and allelic loss in human colorectal cancer.
Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Cables expression was reduced in 65% of primary CRCs. No mutations were detected in 10 exons of Cables in 20 primary colon tumors. Cables promoter was methylated in cell lines with decreased Cables expression and vice versa. 5-Aza-2'-deoxycytidine resulted in increased Cables expression in methylated cell lines. There was a significant correlation between promoter methylation and Cables gene expression in primary colon tumors. Sixty-five percent of primary colon tumors demonstrated chromosome 18q LOH. LOH involving the Cables region was observed in 35% of cases, including those in which more distal portions of chromosome 18q were retained, and Cables expression was decreased in all such cases. Loss of Cables expression in 65% of CRCs suggests that it is a common event in colonic carcinogenesis, with promoter methylation and LOH appearing to be important mechanisms of Cables gene inactivation.
Park
Do Youn
DY
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Sakamoto
Hideo
H
Kirley
Sandra D
SD
Ogino
Shuji
S
Kawasaki
Takako
T
Kwon
Eunjeong
E
Mino-Kenudson
Mari
M
Lauwers
Gregory Y
GY
Chung
Daniel C
DC
Rueda
Bo R
BR
Zukerberg
Lawrence R
LR
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic
C486568:CABLES1 protein, human; D002352:Carrier Proteins; D016213:Cyclins; D010750:Phosphoproteins; D000077209:Decitabine; D001374:Azacitidine