Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells

  • Authors:
    • Silke Götze
    • Monique Coersmeyer
    • Oliver Müller
    • Sonja Sievers
  • View Affiliations

  • Published online on: July 21, 2014     https://doi.org/10.3892/ijo.2014.2550
  • Pages: 1715-1723
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Abstract

Histone deacetylase inhibitors (HDIs) specifically affect cancer cells by inducing cell cycle arrest, activate apoptotic pathways and re-activate epigenetically silenced tumor suppressor genes, but their pleiotropic mode of action is not fully understood. Despite the clinical effects of HDIs in the treatment of hematological malignancies, their potency against solid tumors is still unclear. We investigated the effects and mechanisms of HDI action in colorectal carcinoma cell lines with an activated Wnt signaling pathway, which is implicated in different aspects of tumorigenesis, including cell proliferation, apoptosis, angiogenesis and metastasis. We assessed the effects of HDI treatment in colorectal carcinoma cell lines by measuring histone hyperacetylation, cell viability and expression of Wnt target genes. Upon treatment with HDIs of the hydroxamate class, we found attenuation of Wnt signaling with concomitant induction of apoptosis and colorectal cancer cell death. Strikingly, the effects of HDIs on Wnt signaling were independent of histone hyperacetylation, thus we investigated the role of non-histone target proteins of histone deacetylases (HDACs). The compounds TSA and SAHA induced a rapid proteasome-dependent depletion of the Wnt transcription factor TCF7L2, which may be mediated by inhibition of HDAC 6 and 10. Our findings provide a molecular rationale for the use of HDIs against colorectal carcinomas with activated Wnt signaling.
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October 2014
Volume 45 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Götze, S., Coersmeyer, M., Müller, O., & Sievers, S. (2014). Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells. International Journal of Oncology, 45, 1715-1723. https://doi.org/10.3892/ijo.2014.2550
MLA
Götze, S., Coersmeyer, M., Müller, O., Sievers, S."Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells". International Journal of Oncology 45.4 (2014): 1715-1723.
Chicago
Götze, S., Coersmeyer, M., Müller, O., Sievers, S."Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells". International Journal of Oncology 45, no. 4 (2014): 1715-1723. https://doi.org/10.3892/ijo.2014.2550