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Article

HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer

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Center for Physiology, Pathophysiology and Biophysics-Salzburg and Nuremberg, Institute for Physiology and Pathophysiology-Salzburg, Paracelsus Medical University, Strubergasse 22, 5020 Salzburg, Austria
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Department of Internal Medicine I, University Clinics Salzburg, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
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Ludwig Boltzmann Institute for Arthritis und Rehabilitation, Paracelsus Medical University, Strubergasse 22, 5020 Salzburg, Austria
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School of Medical Sciences, Kathmandu University, Kavreplanchowk, Dhulikhel 45200, Nepal
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Department of Surgery, University Clinics Salzburg, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
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Institute of Pathology, University Clinics Salzburg, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
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Cancer Cluster Salzburg, 5020 Salzburg, Austria
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Author to whom correspondence should be addressed.
Academic Editors: Claudio Pisano and John M. Mariadason
Cancers 2021, 13(15), 3862; https://doi.org/10.3390/cancers13153862
Received: 24 June 2021 / Accepted: 27 July 2021 / Published: 31 July 2021
(This article belongs to the Special Issue Targeting Histone Deacetylases in Cancer)
Biliary tract cancer (BTC) is a rare disease with dismal outcomes. Therefore, the investigation of new therapeutic targets is urgently required. In this study, we demonstrate that histone deacetylases (HDACs) are expressed in BTC cell lines and that treatment of BTC cells with different HDAC class inhibitors reduces cell viability. Specifically, we found that BTC cells are vulnerable to the HDAC class I inhibitor romidepsin. Treatment with romidepsin resulted in apoptotic cell death of BTC cells and reduced HDAC activity. Furthermore, romidepsin augmented the cytotoxic effect of the standard chemotherapeutic cisplatin. HDAC class I proteins were also expressed in BTC patient samples. We detected that BTC patients with high HDAC-2-expressing tumors showed a significantly shorter survival. In summary, we were able to demonstrate that BTC cells are vulnerable to HDAC inhibition and that the HDAC class I inhibitor romidepsin might be a promising anti-BTC substance.
Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients. View Full-Text
Keywords: histone deacetylase inhibitor; biliary tract cancer; romidepsin; HDAC 1; HDAC 2; HDAC class I histone deacetylase inhibitor; biliary tract cancer; romidepsin; HDAC 1; HDAC 2; HDAC class I
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MDPI and ACS Style

Mayr, C.; Kiesslich, T.; Erber, S.; Bekric, D.; Dobias, H.; Beyreis, M.; Ritter, M.; Jäger, T.; Neumayer, B.; Winkelmann, P.; Klieser, E.; Neureiter, D. HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer. Cancers 2021, 13, 3862. https://doi.org/10.3390/cancers13153862

AMA Style

Mayr C, Kiesslich T, Erber S, Bekric D, Dobias H, Beyreis M, Ritter M, Jäger T, Neumayer B, Winkelmann P, Klieser E, Neureiter D. HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer. Cancers. 2021; 13(15):3862. https://doi.org/10.3390/cancers13153862

Chicago/Turabian Style

Mayr, Christian, Tobias Kiesslich, Sara Erber, Dino Bekric, Heidemarie Dobias, Marlena Beyreis, Markus Ritter, Tarkan Jäger, Bettina Neumayer, Paul Winkelmann, Eckhard Klieser, and Daniel Neureiter. 2021. "HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer" Cancers 13, no. 15: 3862. https://doi.org/10.3390/cancers13153862

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