Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells
Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells
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操纵组蛋白乙酰化可导致血管肉瘤细胞的抗肿瘤作用
DOI：
10.1111/vco.12840
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发表时间：
2022
影响因子：
2.1
通讯作者：
Kimura Takashi
中科院分区：
文献类型：
--
作者：
Suzuki Tamami;Aoshima Keisuke;Yamazaki Jumpei;Kobayashi Atsushi;Kimura Takashi
犬血管肉瘤（HSA）是一种来源于内皮细胞的恶性肿瘤。由于对其发病机制缺乏了解，尚未开发出有效的治疗方法。组蛋白乙酰化是一种表观遗传修饰，与癌症发病机制密切相关。通过组蛋白脱乙酰酶抑制剂（HDACi）或溴结构域和末端外结构域抑制剂（BETi）操纵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中的作用仍然未知。本研究的目的是探讨组蛋白乙酰化在HSA发病机制中的作用，使用两种HDACi，辛二酰异羟肟酸（SAHA）和丙戊酸（VPA），以及一种BETi，JQ 1，在体外和体内。组蛋白乙酰化水平在细胞系中很高，在临床病例中是异质的。SAHA和JQ1诱导HSA细胞系的凋亡。用SAHA和VPA处理的HSA细胞系上调炎症相关基因并吸引巨噬细胞系RAW 264细胞，这表明SAHA和VPA可以影响免疫反应。JQ1在HSA细胞系中刺激自噬并抑制细胞周期。最后，我们证明JQ1抑制体内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HSA治疗的替代药物。虽然需要进一步的研究，我们的研究表明，组蛋白乙酰化的失调可能参与HSA恶性肿瘤。
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 vitroandin 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 proliferationin vivoalthough 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.