HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis

Sergio A. Gradilone, Stefan Habringer, Tatyana V. Masyuk, Brynn N. Howard, Anatoliy I. Masyuk, Nicholas F La Russo

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)600-608
Number of pages9
JournalAmerican Journal of Pathology
Volume184
Issue number3
DOIs
StatePublished - Mar 2014

Fingerprint

Histone Deacetylases
Cysts
Cell Cycle
Liver
Pharmacology
Cilia
Biliary Tract
Growth
Liver Diseases
Fibrosis
Epithelium
Animal Models
Mutation
Polycystic liver disease
Genes
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. / Gradilone, Sergio A.; Habringer, Stefan; Masyuk, Tatyana V.; Howard, Brynn N.; Masyuk, Anatoliy I.; La Russo, Nicholas F.

In: American Journal of Pathology, Vol. 184, No. 3, 03.2014, p. 600-608.

Research output: Contribution to journalArticle

Gradilone, Sergio A. ; Habringer, Stefan ; Masyuk, Tatyana V. ; Howard, Brynn N. ; Masyuk, Anatoliy I. ; La Russo, Nicholas F. / HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. In: American Journal of Pathology. 2014 ; Vol. 184, No. 3. pp. 600-608.
@article{4b145aa633414580a91483b43fca579f,
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.",
author = "Gradilone, {Sergio A.} and Stefan Habringer and Masyuk, {Tatyana V.} and Howard, {Brynn N.} and Masyuk, {Anatoliy I.} and {La Russo}, {Nicholas F}",
year = "2014",
month = "3",
doi = "10.1016/j.ajpath.2013.11.027",
language = "English (US)",
volume = "184",
pages = "600--608",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis

AU - Gradilone, Sergio A.

AU - Habringer, Stefan

AU - Masyuk, Tatyana V.

AU - Howard, Brynn N.

AU - Masyuk, Anatoliy I.

AU - La Russo, Nicholas F

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84894135264&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894135264&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2013.11.027

DO - 10.1016/j.ajpath.2013.11.027

M3 - Article

C2 - 24434010

AN - SCOPUS:84894135264

VL - 184

SP - 600

EP - 608

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 3

ER -