title: HDAC1 and Klf4 interplay critically regulates human myeloid leukemia cell proliferation.
abstract: Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis. Further, knockdown of HDAC1 in leukemia cells K562, HL-60, and U937 significantly increased Klf4 expression and inhibited cell cycle progression and cell proliferation, similar results were found for HDAC inhibitors (VPA and mocetinostat). Moreover, overexpression or knockdown of Klf4 could markedly block the effects of HDAC1 overexpression or knockdown on leukemia cells in vitro and in vivo, respectively. Mechanistic analyses demonstrated that HDAC1 and Klf4 competitively bound to the promoter region of Klf4 and oppositely regulated Klf4 expression in myeloid leukemia. We identified HDAC1 as a potential specific target for repressing cell proliferation and inducing cell cycle arrest through interplay and modulation of Klf4 expression, suggests that HDAC1 and Klf4 are potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia.
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Population & Quantitative Genetics, Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Song
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016329:Sp1 Transcription Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1