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showing antitumor effects on various cancers, among other functions. In this work, we investigated the role of butyrate on CCA cells proliferation and migration, and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation
and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced
cell proliferation in HuCCT1 and KMCH cells but,
on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations.
In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented
the previously described effects of HDAC6 inhibitors that we discovered on CCA cells proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration, and enhanc- es the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
Cholangiocyte Ciliary Defects Induce Sustained Epidermal Growth Factor Receptor Signaling.
A broad group of diseases have defects in their cellular antennae, i.e. the primary cilium. Polycystic liver diseases, which are rare genetic disorders,
are primarily caused by mutations in PKD1, PKD2, PKHD1, and other genes whose products are linked
Working model. CCA cells show reduced ciliary expression due to the overexpression of the deacety- lases HDAC6 and SIRT1 that target the ciliary axon- eme among other functions. The loss of primary cilia induces cell proliferation, migration, and EMT. The combined treatment with butyrate and ACY-1215 synergistically decreases proliferation, migration, and EMT by directly restoring ciliary expression and affecting the signaling pathways downstream these organelles that normally repress cell growth, and indirectly by SIRT1-induced epigenetics regulation.
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to malfunctions of the primary cilia, leading to chronic liver dysfunction. Furthermore, as mentioned before, bile duct cancer cells are also associated with defective ciliary expression. The epidermal growth factor receptor (EGFR) signaling pathway regulates growth and proliferation in almost all human cells, and aberrant EGFR signaling induces disease progression in tumors and kidney and liver polycystic cells. But why this abnormal activity occurs remains understudied. In this project, we found that the upregulated EGFR-MEK-ERK signaling axis and elevated EGF sensitivity in ciliary- defective cholangio- cytes are related to the inability of EGFR to migrate
to primary cilia. We also found that ligand-mediated activated EGFR migration to the cilia is needed for proper receptor clearance and signal termination. Our study reveals a cellular mechanism for the sustained EGFR signaling observed in polycystic liver diseases and cholangiocarcinoma and provides novel insights for potential therapeutic treatments.
Lab research activities:
https://www.hi.umn.edu/research/research-sections/ cancer-cell-biology-and-translational-research/
ORCID iD: https://orcid.org/0000-0002-1753-3634
Recent Publications:
• Pant, K., & Gradilone, S. A.* (2022). Hepatobiliary Cancers: Progress in Diagnosis, Pathogenesis, and Treatment. Technol Cancer Res Treat, 21, 15330338221097203.
• Gradilone, S., Brunetti-Pierri, N., & Piccolo, P. (2022). Cholangiopathies and the noncoding revolution. Curr Opin Gastroenterol, 38(2), 128-135.
• Pant, K., Richard, S., & Gradilone, S. A.* (2021). Short-Chain Fatty Acid Butyrate Induces Cilia Formation and Potentiates the Effects of HDAC6 Inhibitors in Cholangiocarcinoma Cells. Front Cell Dev Biol, 9, 809382.
• Cao, W., Shen, R., Richard, S., Liu, Y., Jalalirad, M., Cleary, M. P., D’Assoro, A. B., Gradilone,
S. A.,* & Yang, D. Q.* (2022). Inhibition of triple-negative breast cancer proliferation and motility by reactivating p53 and inhibiting overactivated Akt. Oncol Rep, 47(2), 41.
• Pant, K., Peixoto, E., Richard, S., Biswas, A., O’Sullivan, M. G., Giama, N., Ha, Y., Yin, J., Carotenuto, P., Salati, M., Ren, Y., Yang, R., Franco, B., Roberts, L. R., & Gradilone, S. A.* (2021). Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma. Hepatology, 74(6), 3235-3248.
(* Corresponding author.)