Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

Abstract

Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. HSA cell lines treated with SAHA and VPA upregulated inflammatory‐related genes and attracted macrophage cell line RAW264 cells, which suggests that SAHA and VPA can affect immune responses. JQ1 stimulated autophagy and inhibited the cell cycle in HSA cell lines. Finally, we demonstrated that JQ1 suppressed HSA tumour cell proliferation in vivo although SAHA and VPA did not affect tumour growth. These results suggest that BETi can be alternative drugs for HSA treatment. Although further research is required, our study indicated that dysregulation of histone acetylation is likely to be involved in HSA malignancy.

New molecular targets in canine hemangiosarcoma—Comparative review and future of the precision medicine

“…84 Moreover, JQ1 might be effective in vivo in tumour growth suppression, which has not been observed after SAHA and VPA administration. 84 A single case study on the treatment of HSA with SAHA has been published. 85 Indeed, the examined mixed breed dog showed no evidence of metastasis 210 days after splenectomy, and was alive and healthy 1000 days post-splenectomy.…”

“…Rodent model studies indicated that SAHA inhibits the growth and development of solid epithelial tumours without serious side‐effects 82,83 . In a recent study, HDACi (SAHA and valproic acid, VPA) together with bromodomain and extraterminal domain inhibitor (BETi)—JQ1, have been investigated in vitro and in vivo 84 . In HSA cell lines, apoptosis induction, upregulation of inflammation‐related genes, and a general effect on the immune response have been proven.…”

“…In HSA cell lines, apoptosis induction, upregulation of inflammation‐related genes, and a general effect on the immune response have been proven. JQ1 appears effective in autophagy stimulation and cell cycle inhibition 84 . Moreover, JQ1 might be effective in vivo in tumour growth suppression, which has not been observed after SAHA and VPA administration 84 .…”

“…JQ1 appears effective in autophagy stimulation and cell cycle inhibition 84 . Moreover, JQ1 might be effective in vivo in tumour growth suppression, which has not been observed after SAHA and VPA administration 84 . A single case study on the treatment of HSA with SAHA has been published 85 .…”

Molecular Profile of Canine Hemangiosarcoma and Potential Novel Therapeutic Targets

“…Histone acetylation is an epigenetic mechanism of cancer modulation, recently studied for potential targeted therapies [ 45 , 46 ]. One in vitro study has demonstrated its potential for canine HSA: histone acetylation levels were high in canine HSA cell lines and some in vivo cases, suppressed by a bromodomain and extraterminal domain inhibitor (BETi), JQ1 [ 46 ]. The potential for this therapy is still unclear, so new studies are required to characterize it properly.…”