title: 4-Hydroxybenzoic acid derivatives as HDAC6-specific inhibitors modulating microtubular structure and HSP90α chaperone activity against prostate cancer.
abstract: Histone deacetylase (HDAC)6 is a unique isoenzyme targeting specific substrates including α-tubulin and heat shock protein (HSP)90. HDAC6 is involved in protein trafficking and degradation, cell shape and migration. Deregulation of HDAC6 activity is associated with a variety of diseases including cancer leading to a growing interest for developing HDAC6 inhibitors. Here, we identified two new structurally related 4-hydroxybenzoic acids as selective HDAC6 inhibitors reducing proliferation, colony and spheroid formation as well as viability of prostate cancer cells. Both compounds strongly enhanced α-tubulin acetylation leading to remodeling of microtubular organization. Furthermore, 4-hydroxybenzoic acids decreased HSP90α regulation of the human androgen receptor in prostate cancer cells by increasing HSP90α acetylation levels. Collectively, our data support the potential of 4-hydroxybenzoic acid derivatives as HDAC6-specific inhibitors with anti-cancer properties.
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Carole
authors.initials: C
authors.lastname: Seidel
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnekenburger
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Aloran
authors.initials: A
authors.lastname: Mazumder
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Teiten
authors.affiliation: UMR CNRS 7565 SRSMC, Université de Lorraine, 57070 Metz, France.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kirsch
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors.forename: Mario
authors.initials: M
authors.lastname: Dicato
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr.
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000502:physiology*; D010226:Parabens / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D056572:Histone Deacetylase Inhibitors; D010226:Parabens; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C038193:4-hydroxybenzoic acid
keywords: HDAC inhibitor; HDAC6; HSP90α; Microtubular organization; Prostate cancer