MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
Cell Res. 2021 Oct;31(10):1088-1105. doi: 10.1038/s41422-021-00530-9. Epub 2021 Jul 15.
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）作为组织稳态和癌症发展中信号转导的新一类重要调控因子而出现。液-液相分离（LLPS）发生在广泛的生物学过程中，但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，我们揭示了一种与脂质相关的 lncRNA，即小核仁 RNA 宿主基因 9（SNHG9），它作为一种促进肿瘤的 lncRNA，驱动 Large Tumor Suppressor Kinase 1（LATS1）的液滴形成，并抑制 Hippo 通路。在机制上，SNHG9 及其相关的磷酸脂（PA）与 LATS1 的 C 端结构域相互作用，促进 LATS1 的相分离，并抑制 LATS1 介导的 YAP 磷酸化。SNHG9 的缺失抑制了异种移植乳腺癌的生长。临床上，SNHG9 的表达与 YAP 活性和乳腺癌进展呈正相关。总之，我们的研究结果揭示了一种促进肿瘤的 lncRNA（即 SNHG9）通过促进信号激酶（即 LATS1）的液-液相分离，在信号转导和癌症发展中发挥新的调节作用。
