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HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer.
- Source :
-
Cancers [Cancers (Basel)] 2021 Jul 31; Vol. 13 (15). Date of Electronic Publication: 2021 Jul 31. - Publication Year :
- 2021
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Abstract
- 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 IC <subscript>50</subscript> 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.
Details
- Language :
- English
- ISSN :
- 2072-6694
- Volume :
- 13
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Cancers
- Publication Type :
- Academic Journal
- Accession number :
- 34359763
- Full Text :
- https://doi.org/10.3390/cancers13153862