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Multiple mechanisms downregulate CDKN1C in human bladder cancer

Michèle J Hoffmann1, Andrea R Florl, Hans-Helge Seifert

  • 1Urologische Klinik, Heinrich-Heine-Universität, Düsseldorf, Germany.

International Journal of Cancer
|November 20, 2004
PubMed

Insights

Downregulation of the CDKN1C gene (cell cycle inhibitor p57KIP2) is common in advanced urothelial cancers. Multiple mechanisms, including LOH, promoter hypermethylation, and imprinting changes, contribute to its reduced expression.

Area of Science:

  • Oncology
  • Genetics
  • Epigenetics

Background:

  • The CDKN1C gene, encoding the cell cycle inhibitor p57KIP2, is imprinted and located at chromosome 11p15.5.
  • Disturbed CDKN1C expression is implicated in Beckwith-Wiedemann syndrome and various human cancers.
  • Downregulation of CDKN1C is frequently observed in advanced urothelial cancers (TCC).

Purpose of the Study:

  • To investigate the mechanisms responsible for CDKN1C downregulation in TCC.
  • To compare CDKN1C expression in TCC cell lines with normal urothelial cells (UEC).

Main Methods:

  • Analysis of CDKN1C mRNA and p57KIP2 protein expression in TCC cell lines and UEC.
  • Investigation of Loss of Heterozygosity (LOH) at 11p15.5 using polymorphic markers.
  • Bisulfite sequencing to assess CDKN1C promoter methylation.
  • Treatment with the methylation inhibitor 5-aza-2'deoxycytidine.
  • Analysis of imprinting center 2 (IC2) differentially methylated regions (DMRs) and LIT1 RNA expression.

Main Results:

  • CDKN1C mRNA and p57KIP2 protein were diminished in 12/15 TCC lines.
  • LOH at 11p15.5 was identified in 3 cell lines.
  • CDKN1C promoter hypermethylation was detected in several TCC lines, correlating with downregulation in at least one.
  • 5-aza-2'deoxycytidine treatment induced CDKN1C expression.
  • IC2 hypomethylation, associated with LIT1 re-expression, was found in most TCC lines, correlating with CDKN1C downregulation in several.

Conclusions:

  • CDKN1C downregulation in TCC occurs through multiple distinct mechanisms.
  • These mechanisms include LOH, promoter hypermethylation, and altered imprinting.
  • Given its tumor suppressor potential (p57KIP2 induces senescence), CDKN1C is a promising candidate for 11p tumor suppression in TCC.

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