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  SIRT1, a deacetylase known to remove the acetyl group from its target proteins.
We found that: (i) SIRT1 is overexpressed in cholangio- carcinoma patient samples (Figure 2) and CCA cell lines; (ii) the activity of SIRT1 con- trols cilia formation; (iii) the SIRT1-induced ciliary loss in CCA cells is regulated by NAD; (iv) SIRT1 increases proteo- lytic degradation of ciliary proteins leading to ciliary loss; (v) SIRT1 regulates CCA cell growth in a ciliary-depen- dent manner; and (vi) SIRT1
inhibition significantly reduced tumor development in a CCA in vivo orthotopic model. The results of our study provide direct evidence that SIRT1 is affecting cholangiocarcinoma cells proliferation by reducing primary cilia expression. In summary, our in vitro and in vivo experiments using SIRT1 inhibition, showed
Figure 1: Primary cilia are reduced in cholangiocarcinoma. Confocal immunofluorescence for a ciliary markers, acetylated-α-tubulin in red. The cholangiocyte marker CK19 is stained in green and nuclei are stained in blue with DAPI. Cilia are easily appreciated on the bile duct lumen of control normal human tissue but reduced amount of ciliary structures were found on cholangiocarcinoma samples.
a reduction in tumor growth associated with an increased ciliary expression, suggesting that the reestablishment of primary cilia in CCA cells by means of SIRT1 inhibitors may be a potential therapeutic approach. On the basis of our current
and previous studies, we propose the idea that reestablishment of primary cilia and their complex multisensory signals, i.e. ciliotherapy, by targeting proteins and processes involved in ciliary resorption like SIRT1, proteasome, HDAC6, and/or autophagy could inhibit CCA tumor progression. The rapidly developing field of HDACs inhibitors allows to create effective SIRT1 inhibitors including Sirtinol, suggest- ing that SIRT1-specific targeting may have substantial effects. Furthermore, broad-spectrum inhibitors like butyrate may also have potential applications.
Inhibition of triple-negative breast cancer proliferation and motility by reactivating p53 and inhibiting overactivated Akt. Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple-nega-
tive breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, we found that a specific inhibitor of histone deacetylase 6, ACY1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggest that ACY1215 may lead to enhanced transcriptional activity of p53. We also found that ACY1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY1215 displayed synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, we observed that combination of ACY1215 and ATM inhibitors exhib- ited much more potent antitumor activity than the
Figure 2: SIRT1 is overexpressed in Human CCA samples. A, Immuno- histochemistry for SIRT1 in CCA tumor samples compared to surrounding normal tissue in Tissue Microarray slides. B, Quantification of SIRT1 expression in tumor and normal bile ducts by nuclear and cytoplasmic scoring. (* P < 0.05 and ** P < 0.01)
individual compound in xenograft models of breast cancer with mutant p53. Taken together, our results demonstrate that ACY1215 is a novel chemothera- peutic agent that can restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.
 Publications:
• 1-Pant K, Peixoto E, Richard S, Biswas A, O’Sullivan MG, Giama N, Ha Y, Yin J, Carotenuto P, Salati M, Ren Y, Yang R, Franco B, Roberts LR, Gradilone SA. “Histone Deacetylase
SIRT1 promotes loss of primary cilia in Cholangiocarcinoma.” Hepatology, 2021.
• 2-Caballero J, Rivilla I, Herraez E, Briz O, Santos A, Izquierdo-Sanchez L, Lee-Law P, Rodrigues P, Munoz-Garrido P, Jin S, Peixoto E, Richard
S, Gradilone SA, Perugorria M, Esteller M, Bujanda L, Marin J, Banales J, Cossio F. “New synthetic conjugates of ursodeoxycholic acid inhibit cystogenesis in experimental models of polycystic liver disease.” Hepatology, 73(1): 186-203, 2021.
• 3-Pant K, Richard S, Biswas A, Peixoto E, Gradilone SA. “Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma.” Front Med, 7:113, 2020.
 

















































































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