Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.
Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.
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DOI：
10.1096/fj.201901734rr
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发表时间：
2020-03
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已知鞘氨醇激酶 2 (SphK2) 可使核鞘脂代谢物磷酸化，生成 1-磷酸鞘氨醇 (S1P)。核S1P参与基因表达的表观遗传调控；然而，其根本机制尚不清楚。在这项工作中，我们确定了核S1P和SphK2在调节缺氧反应主转录因子HIF-1α/2α中的作用及其在乳腺癌中的功能，重点是三阴性乳腺癌（TNBC）。我们已经证明 SphK2 与蛋白质复合物中的 HIF-1α 相关，并且在 HIF 靶基因的启动子处富集，包括血管内皮生长因子 VEGF，在那里它增强局部组蛋白 H3 乙酰化和转录。 S1P 特异性结合 HIF-1α 的 PAS 结构域。与健康乳腺组织样本相比，转移性雌激素受体阳性 (ER+) 和 TNBC 临床组织样本中的 SphK2 和 HIF-1α 表达水平升高。为了确定 SphK2 在细胞核中形成 S1P 是否是 HIF 功能的关键调节因子，我们使用临床前 TNBC 异种移植小鼠模型和现有的选择性 SphK2 抑制剂 K-145 发现，体内核 S1P、组蛋白乙酰化、HIF-1α 表达和 TNBC 肿瘤生长均减少。我们的结果表明，细胞核中的 S1P 和 SphK2 与乳腺癌进展相关的 HIF-1α/2α 功能的调节有关，并可能提供潜在的治疗靶点。
Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine-1-phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia-responsive master transcription factors HIF-1α/2α, and their functions in breast cancer, with a focus on triple-negative breast cancer (TNBC). We have shown SphK2 is associated with HIF-1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor VEGF, where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF-1α. SphK2 and HIF-1α expression levels are elevated in metastatic estrogen receptor-positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K-145, that nuclear S1P, histone acetylation, HIF-1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF-1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.