title: CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status.
abstract: We previously reported that CG0006, a novel hydroxamate-based pan-histone deacetylase inhibitor (HDACI), suppresses the growth of human cancer cells. Here, we tested the ability of CG0006 to inhibit breast cancer cell proliferation in relation to estrogen receptor (ER) status, and examined changes in the expression of cell-cycle regulatory proteins. CG0006 effects on the proliferation of multiple human cancer cell lines were tested using MTT and MTS assays. Changes in estrogen-signaling proteins and cell-cycle regulatory proteins were examined by western blotting and quantitative RT-PCR, and cell-cycle effects were tested using flow cytometry. CG0006 increased histone H3 and H4 acetylation, up-regulated p21 protein, and promoted cell-cycle arrest, inducing G(2)/M-phase accumulation in ER-positive MCF7 cells, and G(1)- and G(2)/M-phase accumulation in ER-negative MDA-MB-231 cells. In both cell types, CG0006 treatment (1 μM) reduced the levels of the estrogen-signaling proteins ERα and cyclin D1, and promoted massive degradation of cell-cycle regulatory proteins. CG0006 down-regulated the histone deacetylase HDAC6 at the protein level in association with a subsequent increase in Hsp90 and α-tubulin acetylation. HDAC6 depletion using small interfering RNA produced a protein-degradation phenotype similar to that of CG0006 treatment. These findings suggest that CG0006 inhibits breast cancer cell growth by two different pathways: a histone acetylation-dependent pathway, and a non-epigenetic pathway that disrupts chaperone function.
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea.
authors.forename: Hyun Mi
authors.initials: HM
authors.lastname: Kim
authors.forename: Choung-Soo
authors.initials: CS
authors.lastname: Kim
authors.forename: Je-Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jang
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Seonggu
authors.initials: S
authors.lastname: Ro
authors.forename: Young-Lan
authors.initials: YL
authors.lastname: Hyun
authors.forename: Jene
authors.initials: J
authors.lastname: Choi
mesh_terms: D000107:Acetylation; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D053453:Caspase 9 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D014176:Protein Biosynthesis; D059748:Proteolysis; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018931:Antineoplastic Agents, Hormonal; D053453:Caspase 9; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D020928:Mitogen-Activated Protein Kinases; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C545965:CG 0006; C506487:ESR1 protein, human; C508053:ERBB2 protein, human; C506433:CASP9 protein, human; C433811:HDAC6 protein, human