HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer
HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer
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HIF1α 乳酰化增强 KIAA1199 转录，促进前列腺癌中的血管生成和血管生成拟态
DOI：
10.1016/j.ijbiomac.2022.10.014
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发表时间：
2022-11-05
影响因子：
8.2
通讯作者：
Zhang, Peng
中科院分区：
文献类型：
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作者：
Luo, Yongwen;Yang, Zhonghua;Zhang, Peng
前列腺癌（PCa）是成年男性中最常见的恶性肿瘤之一。然而，PCa对基于多激酶抑制剂的抗血管生成疗法具有抵抗力，其机制和有效靶向仍不清楚。在这项研究中，单细胞和批量转录组数据集分析表明，透明质酸 (HA) 结合蛋白 KIAA1199 参与糖酵解、缺氧和血管生成途径。此外，PCa 组织中 KIAA1199 表达的增强与肿瘤分期、缺氧诱导因子 (HIF)-1 α 过表达以及血管生成标志物呈正相关。管形成、蛋白质印迹、酶联免疫吸附测定和体内肿瘤发生结果表明，KIAA1199 沉默通过增加信号 3A (sema3A) 表达同时降低 VEGFA、VE-钙粘蛋白、磷酸化 EphA2 和解聚 HA 水平，在体外和体内显着抑制血管生成和血管生成拟态 (VM)。还发现 KIAA1199 过表达可通过增加 VEGFA 分泌来促进血管生成和 VM，然而，HA 生物合成抑制剂 4-methylumbelliferone (4MU) 可以逆转这种活性。此外，双荧光素酶和 ChIP-PCR 显示 HIF1 α 是 KIAA1199 的转录增强子，而通过单羧酸转运蛋白 1 (MCT1) 将乳酸导入 PCa 细胞，通过 HIF1 α 乳酸化在常氧条件下稳定 HIF1 α。我们的研究结果可能有助于更好地了解血管生成和前列腺癌的有希望的治疗靶点。
Prostate cancer (PCa) is one of the most prevalent malignancies in adult males. However, PCa is resistant to multi-kinase inhibitors-based anti-angiogenic therapies, and the mechanism and effective targeting thereof remains unclear. In this study, single-cell and bulk-transcriptomic datasets analysis revealed that KIAA1199, a hyaluronic acid (HA) binding protein, was involved in glycolysis, hypoxia and angiogenesis pathways. Moreover, boosted KIAA1199 expression in PCa tissues was positively correlated with tumor stage, hypoxia-inducible factor (HIF)-1 alpha overexpression, as well as angiogenesis markers. Tube formation, Western blot, enzyme-linked immunosorbent assay, and in vivo tumorigenesis results demonstrated that KIAA1199 silencing significantly inhibited angiogenesis and vasculogenic mimicry (VM), both in vitro and in vivo, by increasing semaphoring 3A (sema3A) expression while decreasing expressions of VEGFA, VE-cadherin, phosphorylated EphA2, and depolymerized HA levels. KIAA1199 overexpression was also found to promote angiogenesis and VM via increasing secretory VEGFA, however, this activity could be reversed by the HA biosynthesis inhibitor 4-methylumbelliferone (4MU). Furthermore, dual-luciferase and ChIP-PCR revealed that HIF1 alpha is the transcriptional enhancer of KIAA1199, while lactate imported to PCa cells by monocarboxylate transporter 1 (MCT1) stabilizes HIF1 alpha under normoxia via HIF1 alpha lactylation. Our findings may provide a better understanding of angiogenesis and a promising therapeutic target of PCa.