title: The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer.
abstract: HPP1 (hyperplastic polyposis protein 1), a tumor suppressor gene, is downregulated by promoter hypermethylation in a number of tumor types including colon cancer. c-Myc is also known to play a role in the suppression of HPP1 expression via binding to a promoter region cognate E-box site. The contribution of histone deacetylation as an additional epigenetic mechanism and its potential interplay with c-Myc in the transcriptional regulation of HPP1 are unknown. We have shown that the treatment of the HPP1-non-expressing colon cancer cell lines, HCT116 and DLD-1 with HDAC inhibitors results in re-expression of HPP1. RNAi-mediated knockdown of c-Myc as well as of HDAC2 and HDAC3 in HCT116 and of HDAC1 and HDAC3 in DLD-1 also resulted in significant re-expression of HPP1. Co-immunoprecipitation (IP), chromatin IP (ChIP), and sequential ChIP experiments demonstrated binding of c-Myc to the HPP1 promoter with recruitment of and direct interaction with HDAC3. In summary, we have demonstrated that c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. Our findings may lead to a greater biologic understanding for the application of targeted use of HDAC inhibitors for anti-cancer therapy.
authors.affiliation: Department of Gastrointestinal Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA; Department of Pancreatic Oncology; Cancer Institute and Hospital of Tianjin Medical University; Tianjin, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: Abul
authors.initials: A
authors.lastname: Elahi
authors.affiliation: Department of Gastrointestinal Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: Abidemi
authors.initials: A
authors.lastname: Ajidahun
authors.affiliation: Department of Gastrointestinal Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: Whalen
authors.initials: W
authors.lastname: Clark
authors.affiliation: Department of Gastrointestinal Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hernandez
authors.affiliation: Department of Molecular Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Achille
authors.affiliation: Department of Pancreatic Oncology; Cancer Institute and Hospital of Tianjin Medical University; Tianjin, PR China.
authors.forename: Ji-hui
authors.initials: JH
authors.lastname: Hao
authors.affiliation: Department of Molecular Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.affiliation: Department of Gastrointestinal Oncology; H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL USA.
authors.forename: David
authors.initials: D
authors.lastname: Shibata
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D000099186:Histone Deacetylase 3; C489427:MYC protein, human; C423567:TMEFF2 protein, human
keywords: HPP1; Myc; colon cancer; epigenetics; histone acetylase; histone deacetylase inhibitors