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

Cell Res. 2021 Oct;31(10):1088-1105. doi: 10.1038/s41422-021-00530-9. Epub 2021 Jul 15.

Abstract

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Phenomena*
  • Cell Line, Tumor
  • Cell Proliferation
  • Hippo Signaling Pathway
  • Humans
  • Phosphatidic Acids
  • Phosphoproteins / genetics
  • Protein Serine-Threonine Kinases / genetics
  • RNA, Long Noncoding* / genetics
  • Signal Transduction
  • YAP-Signaling Proteins

Substances

  • Phosphatidic Acids
  • Phosphoproteins
  • RNA, Long Noncoding
  • YAP-Signaling Proteins
  • LATS1 protein, human
  • Protein Serine-Threonine Kinases