Multiple mechanisms downregulate CDKN1C in human bladder cancer
Open Access
- 18 November 2004
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 114 (3), 406-413
- https://doi.org/10.1002/ijc.20749
Abstract
Expression of the imprinted CDKN1C gene at chromosome 11p15.5 encoding the cell cycle inhibitor p57KIP2 is disturbed in Beckwith‐Wiedemann syndrome and in several human cancers by different mechanisms. Many advanced urothelial cancers (TCC) display downregulation of CDKN1C expression. The responsible mechanisms were investigated in TCC cell lines, with cultured normal urothelial cells (UEC) as controls. CDKN1C mRNA expression was diminished in 12/15 TCC lines and p57KIP2 protein was decreased accordingly. Because CDKN1C is expressed from the maternal allele only, LOH at 11p15.5 represents one mechanism of downregulation. In 3 cell lines, several polymorphic markers flanking CDKN1C were homozygous compatible with this mechanism. Hypermethylation of the CDKN1C promoter, a reported cause of downregulation in other cancers, was detected by bisulfite sequencing in several cell lines and appeared associated with downregulation in at least one cell line. The methylation inhibitor 5‐aza‐2′deoxycytidine induced CDKN1C expression in this cell line and others. A third reported mechanism involves a switch of both alleles toward a paternal imprinting pattern, indicated by hypomethylation of a differentially methylated region (DMR) in the imprinting center (IC2). This hypomethylation was detected in most TCC lines, and was associated with re‐expression of the non‐coding LIT1 RNA and with downregulation of CDKN1C in several. Thus, CDKN1C downregulation in TCC seems to occur by several different mechanisms. This finding and the ability of p57KIP2 to induce senescence in urothelial cells make CDKN1C a good candidate for a tumor suppressor at 11p in TCC.Keywords
This publication has 26 references indexed in Scilit:
- A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencerHuman Molecular Genetics, 2003
- A Differentially Methylated Imprinting Control Region within the Kcnq1 Locus Harbors a Methylation-sensitive Chromatin InsulatorPublished by Elsevier BV ,2002
- Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cellsOncogene, 2001
- Sequence and functional comparison in the Beckwith-Wiedemann region: implications for a novel imprinting centre and extended imprintingHuman Molecular Genetics, 2000
- Sequence and Comparative Analysis of the Mouse 1-Megabase Region Orthologous to the Human 11p15 Imprinted DomainGenome Research, 2000
- Decreased expression of p57KIP2 mRNA in human bladder cancerBritish Journal of Cancer, 2000
- New p57 KIP2 mutations in Beckwith-Wiedemann syndromeHuman Genetics, 1997
- Multiple genetic loci within 11p15 defined by Beckwith-Wiedemann syndrome rearrangement breakpoints and subchromosomal transferable fragments.Proceedings of the National Academy of Sciences of the United States of America, 1995
- Deletion mapping of chromosome II in carcinoma of the bladderGenes, Chromosomes and Cancer, 1995
- Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution.Genes & Development, 1995