Class I histone deacetylase inhibitor suppresses vasculogenic mimicry by enhancing the expression of tumor suppressor and anti-angiogenesis genes in aggressive human TNBC cells
Class I histone deacetylase inhibitor suppresses vasculogenic mimicry by enhancing the expression of tumor suppressor and anti-angiogenesis genes in aggressive human TNBC cells
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DOI：
10.3892/ijo.2019.4796
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发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
Hait, Nitai C.
中科院分区：
文献类型：
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作者：
Maiti, Aparna;Qi, Qianya;Hait, Nitai C.
三阴性乳腺癌（TNBC）细胞形成不依赖于血管生成的血管样结构来生存，称为血管生成拟态（VM），导致癌症患者预后不良。核定位 I 类组蛋白脱乙酰酶 (HDAC)，特别是 HDAC 1、2、3 脱乙酰染色质组蛋白，在癌症中过度表达，并通过表观遗传学调节参与癌症发生和进展的基因的表达。特定的 HDAC 抑制剂恩替司他 (entinostat) 已被证明可以减弱 TNBC 中的肿瘤进展和转移。在本研究中，我们假设恩替司他会增强抗血管生成和肿瘤抑制基因的表达，从而抑制 3D Matrigel 细胞培养临床前模型中 TNBC 细胞中的 VM 结构。我们的数据表明，侵袭性三阴性 MDA-MB-231、LM2-4 和 BT-549 乳腺癌细胞（而非侵袭性差的管腔 MCF-7 细胞）有效地经历了基质相关 VM 形成。当与基质胶混合并在低附着组织培养板中培养时，大约 80% 具有干细胞表型潜力的 TNBC 细胞形成血管样结构。 VM形成的分子机制相当复杂，VM形成细胞中血管生成抑制基因下调，促血管生成基因上调。我们的数据显示，用恩替司他表观遗传学治疗TNBC VM表型细胞导致抗血管生成基因、丝氨酸蛋白酶抑制剂家族F成员1（SERPINF1）和血小板反应蛋白2（THBS2）的重新表达，以及肿瘤抑制基因、磷酸酶和张力蛋白同源物（PTEN）和p21的重新表达，并减少VM结构。我们还发现，用恩替司他治疗 TNBC VM 表型细胞可下调血管内皮生长因子 A (VEGF-A) 以及上皮间质转化 (EMT) 相关基因波形蛋白和 β-连环蛋白的表达。 METABIRC 和 TCGA 乳腺癌队列 mRNA 表达数据分析显示，抗血管生成相关基因 THBS2、SERPINF1 和丝氨酸蛋白酶抑制剂家族 B 成员 5 (SERPINB5) 以及肿瘤抑制基因 PTEN 的高表达与乳腺癌患者更好的总生存 (OS) 相关。总而言之，本研究的结果表明 HDAC 1、2、3 部分有助于 TNBC 细胞中 VM 的形成；因此，HDACs可能是TNBC的重要治疗靶点。
Triple-negative breast cancer (TNBC) cells form angiogenesis-independent vessel-like structures to survive, known as vasculogenic mimicry (VM), contributing to a poor prognosis for cancer patients. Nuclear localized class I histone deacetylases (HDACs) enzymes, particularly HDACs 1, 2, 3 deacetylate chromatin histones, are overexpressed in cancers and epigenetically regulate the expression of genes involved in cancer initiation and progression. The specific HDAC inhibitor, entinostat, has been shown to attenuate tumor progression and metastasis in TNBC. In this study, we hypothesized that entinostat would enhance the expression of anti-angiogenic and tumor suppressor genes and would thus suppress VM structures in TNBC cells in a 3D Matrigel cell culture preclinical model. Our data indicated that invasive triple-negative MDA-MB-231, LM2-4 and BT-549 breast cancer cells, but not poorly invasive luminal MCF-7 cells, efficiently underwent matrix-associated VM formation. Approximately 80% of TNBC cells with the stem cell phenotype potential formed vessel-like structures when mixed with Matrigel and cultured in the low attachment tissue culture plate. The molecular mechanisms of VM formation are rather complex, while angiogenesis inhibitor genes are downregulated and pro-angiogenesis genes are upregulated in VM-forming cells. Our data revealed that treatment of the TNBC VM phenotype cells with entinostat epigenetically led to the re-expression of the anti-angiogenic genes, serpin family F member 1 (SERPINF1) and thrombospondin 2 (THBS2), and to that of the tumor suppressor genes, phosphatase and tensin homolog (PTEN) and p21, and reduced VM structures. We also found that treatment of the TNBC VM phenotype cells with entinostat downregulated the expression of vascular endothelial growth factor A (VEGF-A), and that of the epithelial-mesenchymal transition (EMT)-related genes, Vimentin and beta-catenin. METABIRC and TCGA breast cancer cohort mRNA expression data analysis revealed that a high expression of the anti-angiogenesis-associated genes, THBS2, SERPINF1 and serpin family B member 5 (SERPINB5), and of the tumor suppressor gene, PTEN, was associated with a better overall survival (OS) of breast cancer patients. Taken together, the findings of this study demonstrate that HDACs 1, 2, 3 partly contribute to VM formation in TNBC cells; thus, HDACs may be an important therapeutic target for TNBC.