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.