title: HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis.
abstract: Polycystic liver disease (PLD) is a member of the cholangiopathies, a group of liver diseases in which cholangiocytes, the epithelia lining of the biliary tree, are the target cells. PLDs are caused by mutations in genes involved in intracellular signaling pathways, cell cycle regulation, and ciliogenesis, among others. We previously showed that cystic cholangiocytes have abnormal cell cycle profiles and malfunctioning cilia. Because histone deacetylase 6 (HDAC6) plays an important role in both cell cycle regulation and ciliary disassembly, we examined the role of HDAC6 in hepatic cystogenesis. HDAC6 protein was increased sixfold in cystic liver tissue and in cultured cholangiocytes isolated from both PCK rats (an animal model of PLD) and humans with PLD. Furthermore, pharmacological inhibition of HDAC6 by Tubastatin-A, Tubacin, and ACY-1215 decreased proliferation of cystic cholangiocytes in a dose- and time-dependent manner, and inhibited cyst growth in three-dimensional cultures. Importantly, ACY-1215 administered to PCK rats diminished liver cyst development and fibrosis. In summary, we show that HDAC6 is overexpressed in cystic cholangiocytes both in vitro and in vivo, and its pharmacological inhibition reduces cholangiocyte proliferation and cyst growth. These data suggest that HDAC6 may represent a potential novel therapeutic target for cases of PLD.
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: gradilone.sergio@mayo.edu.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Gradilone
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stefan
authors.initials: S
authors.lastname: Habringer
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Masyuk
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Brynn N
authors.initials: BN
authors.lastname: Howard
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anatoliy I
authors.initials: AI
authors.lastname: Masyuk
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: larusso.nicholas@mayo.edu.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Larusso
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000166:cytology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism; D003560:Cysts / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011743:Pyrimidines; C474316:tubacin; C553587:tubastatin A; C433811:HDAC6 protein, human; C545556:HDAC6 protein, rat; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C572255:ricolinostat