Hypoxia-induced long non-coding RNA DARS-AS1 regulates RBM39 stability to promote myeloma malignancy
Hypoxia-induced long non-coding RNA DARS-AS1 regulates RBM39 stability to promote myeloma malignancy
复制标题
缺氧诱导的长非编码RNA DARS-AS1调节RBM39稳定性促进骨髓瘤恶性
DOI：
10.3324/haematol.2019.218289
复制
发表时间：
2020-06-01
期刊：
影响因子：
10.1
通讯作者：
Yan, Hua
中科院分区：
文献类型：
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作者：
Tong, Jia;Xu, Xiaoguang;Yan, Hua
多发性骨髓瘤是一种恶性浆细胞疾病，其高度依赖于缺氧的骨髓微环境。然而，缺氧导致骨髓瘤发生的潜在机制尚未完全了解。在这里，我们发现骨髓瘤中的长非编码RNA DARS-AS 1被缺氧诱导因子（HIF）-1直接上调。重要的是，DARS-AS 1是骨髓瘤细胞在体外和体内的存活和肿瘤发生所必需的。DARS-AS 1通过结合RNA结合基序蛋白39（RBM 39）发挥其功能，从而阻碍RBM 39与其E3泛素连接酶RNF 147之间的相互作用，并防止RBM 39降解。在骨髓瘤细胞中观察到的RBM 39的过表达与不良预后相关。此外，DARS-AS 1的敲低抑制雷帕霉素信号通路的哺乳动物靶标，这一作用被RBM 39过表达逆转。我们揭示了一种新的HIF-1/DARS-AS 1/RBM 39通路与骨髓瘤的发病机制有关。因此，靶向DARS-AS 1/RBM 39可能代表了对抗骨髓瘤的新策略。
Multiple myeloma is a malignant plasma-cell disease, which is highly dependent on the hypoxic bone marrow microenvironment. However, the underlying mechanisms of hypoxia contributing to myeloma genesis are not fully understood. Here, we show that long non-coding RNA DARS-AS1 in myeloma is directly upregulated by hypoxia inducible factor (HIF)-1. Importantly, DARS-AS1 is required for the survival and tumorigenesis of myeloma cells both in vitro and in vivo. DARS-AS1 exerts its function by binding RNA-binding motif protein 39 (RBM39), which impedes the interaction between RBM39 and its E3 ubiquitin ligase RNF147, and prevents RBM39 from degradation. The overexpression of RBM39 observed in myeloma cells is associated with poor prognosis. Furthermore, knockdown of DARS-AS1 inhibits the mammalian target of rapamycin signaling pathway, an effect that is reversed by RBM39 overexpression. We reveal that a novel HIF-1/DARS-AS1/RBM39 pathway is implicated in the pathogenesis of myeloma. Targeting DARS-AS1/RBM39 may, therefore, represent a novel strategy to combat myeloma.