Suzuki Tamami, Aoshima Keisuke, Yamazaki Jumpei, Kobayashi Atsushi, Kimura Takashi
Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
Vet Comp Oncol. 2022 Dec;20(4):805-816. doi: 10.1111/vco.12840. Epub 2022 Jun 1.
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.
犬血管肉瘤（HSA）是一种源自内皮细胞的恶性肿瘤。由于对其发病机制缺乏了解，目前尚未开发出有效的治疗方法。组蛋白乙酰化作为一种表观遗传修饰，与癌症发病机制高度相关。通过组蛋白去乙酰化酶抑制剂（HDACi）或溴结构域和额外末端结构域抑制剂（BETi）来调控组蛋白乙酰化是治疗各种癌症的一种方法。然而，组蛋白乙酰化在HSA中的作用仍不清楚。本研究旨在使用两种HDACi（辛二酰苯胺异羟肟酸（SAHA）和丙戊酸（VPA））以及一种BETi（JQ1）在体外和体内研究组蛋白乙酰化在HSA发病机制中的作用。细胞系中的组蛋白乙酰化水平较高，而临床病例中的水平则存在异质性。SAHA和JQ1诱导HSA细胞系凋亡。用SAHA和VPA处理的HSA细胞系上调了炎症相关基因，并吸引了巨噬细胞系RAW264细胞，这表明SAHA和VPA可以影响免疫反应。JQ1刺激自噬并抑制HSA细胞系中的细胞周期。最后，我们证明JQ1在体内抑制了HSA肿瘤细胞增殖，尽管SAHA和VPA不影响肿瘤生长。这些结果表明BETi可以作为治疗HSA的替代药物。尽管还需要进一步研究，但我们的研究表明组蛋白乙酰化失调可能与HSA的恶性程度有关。
