Histone Deacetylase SIRT1 promotes loss of primary cilia in Cholangiocarcinoma

Kishor Pant, Estanislao Peixoto, Seth Richard, Aalekhya Sharma Biswas, M. Gerard O’Sullivan, Nasra Giama, Yeonjung Ha, Jun Yin, Pietro Carotenuto, Massimiliano Salati, Yanan Ren, Rendong Yang, Brunella Franco, Lewis R. Roberts, Sergio A. Gradilone

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Background and Aims: Sirtuin 1 (SIRT1) is a complex NAD+-dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA). Approach and Results: A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD -producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1-overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α-tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma-associated oncogene 1, phosphorylated extracellular signal-regulated kinase, and IL-6) expression. Conclusions: In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

Original languageEnglish (US)
Pages (from-to)3235-3248
Number of pages14
JournalHepatology
Volume74
Issue number6
Early online dateJul 29 2021
DOIs
StatePublished - Jul 29 2021

Bibliographical note

Funding Information:
We thank the Mayo Clinic Hepatobiliary SPORE and the Mayo Center for Cell Signaling in Gastroenterology for providing the tissue microarray.

Funding Information:
Supported by National Institutes of Health Grant R01CA183764 (to S.A.G.) and The Hormel Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Part of the study was kindly supported by POR CAMPANIA FESR 2014/2020 grant (project titles “Dalla genomica alla terapia di tumori rari” and “Combattere la resistenza tumorale: piattaforma integrata multidisciplinare per un approccio tecnologico innovativo alle concoterapie”; CUP B61G18000470007) and the Italian Association for Cancer Research (AIRC) (grant no. IG 17711/2015 to B.F.). P.C. is a current recipient of a Marie Skłodowska‐Curie Career Re‐Integration fellowship funded by AIRC and the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 800924).

Publisher Copyright:
© 2021 by the American Association for the Study of Liver Diseases.

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