HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation

C. Jung, R. S. Kim, H. Zhang, S. J. Lee, H. Sheng, Patrick Loehrer, Thomas Gardner, M. H. Jeng, Chinghai Kao

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Mutations in the Wnt signalling cascade are believed to cause aberrant proliferation of colorectal cells through T-cell factor-4 (TCF4) and its downstream growth-modulating factors. HOXB13 is exclusively expressed in prostate and colorectum. In prostate cancers, HOXB13 negatively regulates β-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. To study the role of HOXB13 in colorectal tumorigenesis, we evaluated the expression of HOXB13 in 53 colorectal tumours originated from the distal left colon to rectum with their matching normal tissues using quantitative RT-PCR analysis. Expression of HOXB13 is either lost or diminished in 26 out of 42 valid tumours (62%), while expression of TCF4 RNA is not correlated with HOXB13 expression. TCF4 promoter analysis showed that HOXB13 does not regulate TCF4 at the transcriptional level. However, HOXB13 downregulated the expression of TCF4 and its target gene, c-myc, at the protein level and consequently inhibited β-catenin/TCF-mediated signalling. Functionally, forced expression of HOXB13 drove colorectal cancer (CRC) cells into growth suppression. This is the first description of the downregulation of HOXB13 in CRC and its mechanism of action is mediated through the regulation of TCF4 protein stability. Our results suggest that loss of HOXB13 may be an important event for colorectal cell transformation, considering that over 90% of colorectal tumours retain mutations in the APC/β-catenin pathway.

Original languageEnglish
Pages (from-to)2233-2239
Number of pages7
JournalBritish Journal of Cancer
Volume92
Issue number12
DOIs
StatePublished - Jun 20 2005

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Transcription Factor 7-Like 2 Protein
Transcriptional Activation
Colorectal Neoplasms
Down-Regulation
Catenins
Proto-Oncogene Proteins c-myc
Mutation
Protein Stability
Growth
Rectum
Prostate
Prostatic Neoplasms
Intercellular Signaling Peptides and Proteins
Colon
Carcinogenesis
Cell Proliferation
RNA
Polymerase Chain Reaction

Keywords

  • Colorectal cancer
  • Homeobox gene
  • HOXB13
  • TCF4

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation. / Jung, C.; Kim, R. S.; Zhang, H.; Lee, S. J.; Sheng, H.; Loehrer, Patrick; Gardner, Thomas; Jeng, M. H.; Kao, Chinghai.

In: British Journal of Cancer, Vol. 92, No. 12, 20.06.2005, p. 2233-2239.

Research output: Contribution to journalArticle

Jung, C. ; Kim, R. S. ; Zhang, H. ; Lee, S. J. ; Sheng, H. ; Loehrer, Patrick ; Gardner, Thomas ; Jeng, M. H. ; Kao, Chinghai. / HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation. In: British Journal of Cancer. 2005 ; Vol. 92, No. 12. pp. 2233-2239.
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