TitleHDAC4 promotes growth of colon cancer cells via repression of p21.
Publication TypeJournal Article
Year of Publication2008
AuthorsWilson, Andrew J., Byun Do-Sun, Nasser Shannon, Murray Lucas B., Ayyanar Kanyalakshmi, Arango Diego, Figueroa Maria, Melnick Ari, Kao Gary D., Augenlicht Leonard H., and Mariadason John M.
JournalMol Biol Cell
Date Published2008 Oct
KeywordsAnimals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Down-Regulation, Gene Expression Regulation, Neoplastic, Histone Deacetylases, Humans, Male, Mice, Mice, SCID, Models, Biological, Neoplasm Transplantation, Repressor Proteins, RNA, Small Interfering

<p>The class II Histone deacetylase (HDAC), HDAC4, is expressed in a tissue-specific manner, and it represses differentiation of specific cell types. We demonstrate here that HDAC4 is expressed in the proliferative zone in small intestine and colon and that its expression is down-regulated during intestinal differentiation in vivo and in vitro. Subcellular localization studies demonstrated HDAC4 expression was predominantly nuclear in proliferating HCT116 cells and relocalized to the cytoplasm after cell cycle arrest. Down-regulating HDAC4 expression by small interfering RNA (siRNA) in HCT116 cells induced growth inhibition and apoptosis in vitro, reduced xenograft tumor growth, and increased p21 transcription. Conversely, overexpression of HDAC4 repressed p21 promoter activity. p21 was likely a direct target of HDAC4, because HDAC4 down-regulation increased p21 mRNA when protein synthesis was inhibited by cycloheximide. The importance of p21 repression in HDAC4-mediated growth promotion was demonstrated by the failure of HDAC4 down-regulation to induce growth arrest in HCT116 p21-null cells. HDAC4 down-regulation failed to induce p21 when Sp1 was functionally inhibited by mithramycin or siRNA-mediated down-regulation. HDAC4 expression overlapped with that of Sp1, and a physical interaction was demonstrated by coimmunoprecipitation. Chromatin immunoprecipitation (ChIP) and sequential ChIP analyses demonstrated Sp1-dependent binding of HDAC4 to the proximal p21 promoter, likely directed through the HDAC4-HDAC3-N-CoR/SMRT corepressor complex. Consistent with increased transcription, HDAC4 or SMRT down-regulation resulted in increased histone H3 acetylation at the proximal p21 promoter locus. These studies identify HDAC4 as a novel regulator of colon cell proliferation through repression of p21.</p>

Alternate JournalMol Biol Cell
PubMed ID18632985
PubMed Central IDPMC2555950
Grant ListP30-13330 / / PHS HHS / United States
R01 CA100823 / CA / NCI NIH HHS / United States
U01 CA088104 / CA / NCI NIH HHS / United States
CA-88104 / CA / NCI NIH HHS / United States
R01 CA123316-05 / CA / NCI NIH HHS / United States
CA-123316 / CA / NCI NIH HHS / United States
CA-100823 / CA / NCI NIH HHS / United States
R01 CA123316 / CA / NCI NIH HHS / United States