Abstract
Inappropriate transcriptional repression involving histone deacetylases (HDACs) is a prominent cause for the development of leukemia. We now identify faulty expression of a specific mediator of transcriptional repression in a solid tumor. Loss of the adenomatosis polyposis coli (APC) tumor suppressor induces HDAC2 expression depending on the Wnt pathway and c-Myc. Increased HDAC2 expression is found in the majority of human colon cancer explants, as well as in intestinal mucosa and polyps of APC-deficient mice. HDAC2 is required for, and sufficient on its own to prevent, apoptosis of colonic cancer cells. Interference with HDAC2 by valproic acid largely diminishes adenoma formation in APC(min) mice. These findings point toward HDAC2 as a particularly relevant potential target in cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoma / enzymology*
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Adenoma / pathology
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Adenoma / prevention & control
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / physiology*
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Animals
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Apoptosis / drug effects
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Cell Cycle / drug effects
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Cell Transformation, Neoplastic
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Colorectal Neoplasms / enzymology*
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / prevention & control
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Cytoskeletal Proteins / metabolism
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Histone Deacetylase 2
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Histone Deacetylases / biosynthesis*
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Humans
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Intestinal Mucosa / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Small Interfering / pharmacology
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Repressor Proteins / biosynthesis*
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Trans-Activators / metabolism
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Up-Regulation
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Valproic Acid / pharmacology
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Repressor Proteins
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Trans-Activators
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beta Catenin
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Valproic Acid
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Hdac2 protein, mouse
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Histone Deacetylase 2
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Histone Deacetylases