A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid–liquid phase separation to promote oncogenic YAP signaling

• Published in: Cell research Vol. 31; no. 10; pp. 1088 - 1105
• Main Authors: Li, Rui-Hua, Tian, Tian, Ge, Qi-Wei, He, Xin-Yu, Shi, Cheng-Yu, Li, Jun-Hong, Zhang, Zhen, Liu, Fang-Zhou, Sang, Ling-Jie, Yang, Zuo-Zhen, Liu, Ya-Zhuo, Xiong, Yan, Yan, Qingfeng, Li, Xu, Ju, Huai-Qiang, Liu, Jian, Wang, Liang-Jing, Shao, Jian-Zhong, Wang, Wenqi, Zhou, Tianhua, Lin, Aifu
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.10.2021; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/51; 13/89; 13/95; 14/19; 14/32; 14/35; 631/67/1347; 631/80/86; 64/60; 82/51; 82/80; 82/83; Biological activity; Biological Phenomena; Biomedical and Life Sciences; Breast cancer; Cancer; Cell Biology; Cell Line, Tumor; Cell Proliferation; Hippo Signaling Pathway; Homeostasis; Humans; Kinases; Life Sciences; Lipids; Liquid phases; Nucleoli; Phase separation; Phosphatidic acid; Phosphatidic Acids; Phosphoproteins - genetics; Phosphorylation; Protein Serine-Threonine Kinases - genetics; RNA, Long Noncoding - genetics; Signal processing; Signal Transduction; Signaling; snoRNA; Tumor suppressor genes; Tumors; Xenografts; Xenotransplantation; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/s41422-021-00530-9

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).