The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.
The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.
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DOI：
10.1038/ncb3295
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发表时间：
2016-02
影响因子：
21.3
通讯作者：
Yang L
中科院分区：
文献类型：
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作者：
Lin A;Li C;Xing Z;Hu Q;Liang K;Han L;Wang C;Hawke DH;Wang S;Zhang Y;Wei Y;Ma G;Park PK;Zhou J;Zhou Y;Hu Z;Zhou Y;Marks JR;Liang H;Hung MC;Lin C;Yang L
尽管长非编码RNA(LncRNAs)主要存在于细胞核中，并在许多生物过程中发挥功能，但它们在细胞质信号转导中的潜在作用仍未被发现。在这里，我们发现了一种细胞质LINCCRNA，即长基因间隔长的非编码激酶激活RNA(LINK-A)，它分别通过BRK和LRRK2介导HIF1酪氨酸565位和Ser797位的EGFR：GPNMB异源二聚体依赖的HIF1α磷酸化。这些事件导致HIF1α稳定，HIF1α-p300相互作用，并在常氧条件下激活HIF1α转录程序。在机制上，LINK-A促进BRK向EGFR：GPNMB复合体的募集和BRK激酶的激活。依赖BRK的HIF1Tyr565磷酸化干扰α564羟化，导致常氧条件下HIF1α的稳定。LINK-A和LINK-A依赖的信号通路激活都与TNBC相关，促进乳腺癌糖酵解重编程和肿瘤发生。我们的发现说明了细胞质中的lncRNAs在信号转导中的大小和多样性，并强调了lncRNAs在癌症中的重要作用。
Although long noncoding RNAs (lncRNAs) predominately reside in nuclear and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identified a cytoplasmic lncRNA, Long-Intergenic Noncoding RNA for Kinase Activation (LINK-A), which mediates HB-EGF triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr565 and Ser797 by BRK and LRRK2 respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr565 phosphorylation interferes with Pro564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A and LINK-A-dependent signaling pathway activation correlate with TNBC, promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.