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

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 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.

Novel therapeutic strategies for chronic hepatitis B

“…Therefore, targeting pro-HBV epigenetic changes with the help of epigenetic modifiers could promote cccDNA silencing. Several epigenetic drugs targeting DNA methylation or histone acetylation are in development for treating cancers, including HCC and could be repurposed for CHB [ 140 , 141 ]. For example, AGK2, a histone deacetylase Sirtuin 2 inhibitor, was shown to repress HBV replication in cell lines and transgenic mice [ 142 , 143 ].…”

Involvement of Epigenomic Factors in Bile Duct Cancer

“…[65][66][67] Recently, a drug screen identified romidepsin (FK228), an inhibitor of HDAC1 and HDAC2, as a promising epigenetic drug for biliary tract cancer, reducing cell growth. 68 Both, vorinostat and romidepsin, are FDA-approved HDACis for the treatment of T cell lymphomas.…”

Can We Efficiently Target HDAC in Cancer?

“…Furthermore, HDAC2 expression in human BTC specimen could be used as the diagnostic and prognostic biomarker. From this study, the conclusion could be that HDAC inhibition might be a promising combinatory drug approach in BTC as a cancer entity with dismal prognosis and that the tissue expression levels of HDACs seems to be an interesting biomarker in BTC [ 13 ]. Maria Hernandez-Valladares et al studied the in vivo proteomic/phosphoproteomic effects of all-trans retinoic acid (ATRA) and valproic acid (VP) on primary acute myeloid leukemia cells derived from patients before and during disease-stabilizing treatment.…”

“…Furthermore, HDAC2 expression in human BTC specimen could be used as the diagnostic and prognostic biomarker. From this study, the conclusion could be that HDAC inhibition might be a promising combinatory drug approach in BTC as a cancer entity with dismal prognosis and that the tissue expression levels of HDACs seems to be an interesting biomarker in BTC [ 13 ].…”

“…Regarding the question of this editorial, “Can we efficiently target HDAC in cancer?”, the answer after summarizing the main results and conclusions of the published manuscript in this special issue is a clear “yes”. Yes, we can target HDAC in human cancer in a specific matter in order to adequately induce tumor-related cytotoxicity alone or possibly better in a combinatory strategy [ 13 , 14 , 15 , 16 , 17 ]. However, which issues should be addressed in the future?…”