title: HDAC11 is a novel drug target in carcinomas.
abstract: Inhibition of histone deacetylase (HDAC) activity as stand-alone or combination therapy represents a promising therapeutic approach in oncology. The pan- or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose-limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc-dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT-116 colon, PC-3 prostate, MCF-7 breast and SK-OV-3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor-selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology.
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany. h.deubzer@dkfz.de
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.forename: Marie C
authors.initials: MC
authors.lastname: Schier
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.forename: Marco
authors.initials: M
authors.lastname: Lodrini
authors.forename: Bernard
authors.initials: B
authors.lastname: Haendler
authors.forename: Anette
authors.initials: A
authors.lastname: Sommer
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000201:enzymology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries
chemical_list: D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D053148:Caspase 3; C462506:HDAC11 protein, human; D006655:Histone Deacetylases