HDAC6 inhibition restores ciliary expression and decreases tumor growth

Sergio A. Gradilone, Brynn N. Radtke, Pamela S. Bogert, Bing Q. Huang, Gabriella B. Gajdos, Nicholas F La Russo

Research output: Contribution to journalArticle

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Abstract

Primary cilia are multisensory organelles recently found to be absent in some tumor cells, but the mechanisms of deciliation and the role of cilia in tumor biology remain unclear. Cholangiocytes, the epithelial cells lining the biliary tree, normally express primary cilia and their interaction with bile components regulates multiple processes, including proliferation and transport. Using cholangiocarcinoma as a model, we found that primary cilia are reduced in cholangiocarcinoma by a mechanism involving histone deacetylase 6 (HDAC6). The experimental deciliation of normal cholangiocyte cells increased the proliferation rate and induced anchorage-independent growth. Furthermore, deciliation induced the activation of mitogen-activated protein kinase and Hedgehog signaling, two important pathways involved in cholangiocarcinoma development. We found that HDAC6 is overexpressed in cholangiocarcinoma and overexpression of HDAC6 in normal cholangiocytes induced deciliation and increased both proliferation and anchorage-independent growth. To evaluate the effect of cilia restoration on tumor cells, we targeted HDAC6 by short hairpin RNA (shRNA) or by the pharmacologic inhibitor, tubastatin-A Both approaches restored the expression of primary cilia in cholangiocarcinoma cell lines and decreased cell proliferation and anchorage-independent growth. The effects of tubastatin-A were abolished when cholangiocarcinoma cells were rendered unable to regenerate cilia by stable transfection of IFT88-shRNA Finally, inhibition of HDAC6 by tubastatin-A also induced a significant decrease in tumor growth in a cholangiocarcinoma animal model. Our data support a key role for primary cilia in malignant transformation, provide a plausible mechanism for their involvement, and suggest that restoration of primary cilia in tumor cells by HDAC6 targeting may be a potential therapeutic approach for cholangiocarcinoma.

Original languageEnglish (US)
Pages (from-to)2259-2270
Number of pages12
JournalCancer Research
Volume73
Issue number7
DOIs
StatePublished - Apr 1 2013

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Histone Deacetylases
Cilia
Cholangiocarcinoma
Growth
Neoplasms
Small Interfering RNA
Cell Proliferation
Biliary Tract
Mitogen-Activated Protein Kinases
Bile
Organelles
Transfection
Animal Models
Epithelial Cells
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gradilone, S. A., Radtke, B. N., Bogert, P. S., Huang, B. Q., Gajdos, G. B., & La Russo, N. F. (2013). HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Research, 73(7), 2259-2270. https://doi.org/10.1158/0008-5472.CAN-12-2938

HDAC6 inhibition restores ciliary expression and decreases tumor growth. / Gradilone, Sergio A.; Radtke, Brynn N.; Bogert, Pamela S.; Huang, Bing Q.; Gajdos, Gabriella B.; La Russo, Nicholas F.

In: Cancer Research, Vol. 73, No. 7, 01.04.2013, p. 2259-2270.

Research output: Contribution to journalArticle

Gradilone, SA, Radtke, BN, Bogert, PS, Huang, BQ, Gajdos, GB & La Russo, NF 2013, 'HDAC6 inhibition restores ciliary expression and decreases tumor growth', Cancer Research, vol. 73, no. 7, pp. 2259-2270. https://doi.org/10.1158/0008-5472.CAN-12-2938
Gradilone, Sergio A. ; Radtke, Brynn N. ; Bogert, Pamela S. ; Huang, Bing Q. ; Gajdos, Gabriella B. ; La Russo, Nicholas F. / HDAC6 inhibition restores ciliary expression and decreases tumor growth. In: Cancer Research. 2013 ; Vol. 73, No. 7. pp. 2259-2270.
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