A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid-liquid phase separation to promote oncogenic YAP signaling
A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid-liquid phase separation to promote oncogenic YAP signaling
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DOI：
10.1038/s41422-021-00530-9
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发表时间：
2021-07-15
期刊：
影响因子：
44.1
通讯作者：
Lin, Aifu
中科院分区：
文献类型：
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作者：
Li, Rui-Hua;Tian, Tian;Lin, Aifu
长链非编码RNA（lncRNA）是一类新的重要的信号转导调节因子，在组织稳态和肿瘤的发展。液-液相分离（LLPS）发生在广泛的生物过程中，而其在信号转导中的作用仍然在很大程度上未被破译。在这项研究中，我们发现了一个脂质相关的lncRNA，小核仁RNA宿主基因9（SNHG 9）作为一个促进肿瘤的lncRNA驱动液滴形成的大肿瘤抑制激酶1（LATS 1）和抑制Hippo途径。SNHG 9及其相关的磷脂酸（PA）与LATS 1的C-末端结构域相互作用，促进LATS 1相分离并抑制LATS 1介导的雅普磷酸化。SNHG 9的缺失抑制异种移植物乳腺肿瘤生长。临床上，SNHG 9的表达与雅普活性和乳腺癌进展正相关。总之，我们的结果揭示了肿瘤促进lncRNA的新的调节作用（即，SNHG 9）通过促进信号传导激酶（即，LATS 1）。
Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).