HDAC6-dependent ciliophagy is involved in ciliary loss and cholangiocarcinoma growth in human cells and murine models
| Autor: | Fabrizia Carbone, Andrea Ballabio, Aalekhya Biswas, Kristen M. Thelen, Sujeong Jin, Nunzia Pastore, Brunella Franco, Seth Richard, Sergio A. Gradilone, Estanislao Peixoto, Adrian P. Mansini, Stephanie Holtorf, Manuela Morleo |
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| Přispěvatelé: | Peixoto, E., Jin, S., Thelen, K., Biswas, A., Richard, S., Morleo, M., Mansini, A., Holtorf, S., Carbone, F., Pastore, N., Ballabio, A., Franco, B., Gradilone, S. A. |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Physiology Biology Histone Deacetylase 6 Hydroxamic Acids Cholangiocarcinoma Mice 03 medical and health sciences 0302 clinical medicine Primary cilia Cell Line Tumor Physiology (medical) Autophagy LC3 Animals Humans Cilia Receptor Transcription factor Cargo receptor Cell Proliferation Hepatology Cell growth Cilium Intracellular Signaling Peptides and Proteins Gastroenterology Nuclear Proteins NBR1 HDAC6 Rats Ciliophagy Cell biology Gene Expression Regulation Neoplastic Pyrimidines 030104 developmental biology Cell culture 030220 oncology & carcinogenesis TFEB Hydroxychloroquine Research Article |
| Zdroj: | Am J Physiol Gastrointest Liver Physiol |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | Reduced ciliary expression is reported in several tumors, including cholangiocarcinoma (CCA). We previously showed primary cilia have tumor suppressor characteristics, and HDAC6 is involved in ciliary loss. However, mechanisms of ciliary disassembly are unknown. Herein, we tested the hypothesis that HDAC6-dependent autophagy of primary cilia, i.e., ciliophagy, is the main mechanism driving ciliary disassembly in CCA. Using the cancer genome atlas database, human CCA cells, and a rat orthotopic CCA model, we assessed basal and HDAC6-regulated autophagy levels. The effects of RNA-silencing or pharmacological manipulations of ciliophagy on ciliary expression were assessed. Interactions of ciliary proteins with autophagy machinery was assessed by immunoprecipitations. Cell proliferation was assessed by MTS and IncuCyte. A CCA rat model was used to assess the effects of pharmacological inhibition of ciliophagy in vivo. Autophagy is increased in human CCA, as well as in a rat orthotopic CCA model and human CCA cell lines. Autophagic flux was decreased via inhibition of HDAC6, while it was increased by its overexpression. Inhibition of autophagy and HDAC6 restores cilia and decreases cell proliferation. LC3 interacts with HDAC6 and ciliary proteins, and the autophagy cargo receptor involved in targeting ciliary components to the autophagy machinery is primarily NBR1. Treatment with chloroquine, Ricolinostat (ACY-1215), or their combination decreased tumor growth in vivo. Mice that overexpress the autophagy transcription factor TFEB show a decrease of ciliary number. These results suggest that ciliary disassembly is mediated by HDAC6-regulated autophagy, i.e., ciliophagy. Inhibition of ciliophagy may decrease cholangiocarcinoma growth and warrant further investigations as a potential therapeutic approach. NEW & NOTEWORTHY This work identifies novel targets against primary ciliary disassembly that can lead to new cholangiocarcinoma therapeutic strategies. Furthermore, ciliary loss has been described in different tumors, increasing the significance of our research. |
| Databáze: | OpenAIRE |
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