title: Histone deacetylase inhibitors induce attenuation of Wnt signaling and TCF7L2 depletion in colorectal carcinoma cells.
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.
authors: Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors: Silke
authors: S
authors: Götze
authors: Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
authors: Monique
authors: M
authors: Coersmeyer
authors: University of Applied Sciences, Kaiserslautern, Germany.
authors: Oliver
authors: O
authors: Müller
authors: Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors: Sonja
authors: S
authors: Sievers
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C447828:HDAC10 protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases