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).

长链非编码 RNA (lncRNA) 正在成为组织稳态和癌症发展中信号转导的一类新的重要调节因子。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在很大程度上仍未被破译。在这项研究中，我们发现了一种脂质相关的 lncRNA，即小核仁 RNA 宿主基因 9 ( SNHG9 )，它是一种促肿瘤 lncRNA，可驱动大肿瘤抑制激酶 1 (LATS1) 的液滴形成并抑制 Hippo 通路。从机制上讲，SNHG9及其相关的磷脂酸 (PA) 与 LATS1 的 C 端结构域相互作用，促进 LATS1 相分离并抑制 LATS1 介导的 YAP 磷酸化。SNHG9丢失抑制异种移植乳腺肿瘤的生长。临床上，SNHG9的表达与 YAP 活性和乳腺癌进展呈正相关。总之，我们的结果通过促进信号激酶（即LATS1）的LLPS，揭示了促进肿瘤的lncRNA（即SNHG9 ）在信号转导和癌症发展中的新调节作用。