Functional Study Of LncRNA SNHG9 In Regulating Hippo Signaling And Cancer Progression By Modulating Liquid-liquid Phase Separation

Well-organized homeostatic regulation at the molecular level during tissue and organ development is essential for normal growth and development of the organism.The Hippo signaling pathway generates a signaling cascade amplification response by integrating upstream signals and delivering to nodal kinases such as LAST1 to coordinate organ size and tissue growth in the organism.Dysregulation of the Hippo pathway is associated with abnormal cell proliferation and cancer progression.Previous studies indicated that lnc RNAs were capable of modulating signal transduction and cancer development.In this study,we focus on regulatory and functional mechanisms of lnc RNAs in the Hippo signaling pathway,and explores the potential application value of lnc RNAs in clinical diagnosis and treatment of malignant tumors.We identified a phosphatidic acid-binding lnc RNA SNHG9 during the previous screening,which is significantly upregulated in triple-negative breast cancer cell lines and involved in Hippo signaling activation.We further observed the co-localization of SNHG9,PA and LATS1 in the cell,demonstrating the presence as a ternary complex.SNHG9 could enhance PA-LATS1 interaction and inhibit LATS1-MOB1 complex association and LATS1 phosphorylation levels in mechanism.In addition,lnc RNA SNHG9 was found to promote LATS1 kinase phase separation and further inhibit LATS1 kinase activation,resulting in upregulation of YAP target gene CTGF,CYR61 expression.Further studies confirmed that upregulation of SNHG9 resulted in inactivation of LATS1 kinase,YAP transcriptional activation,and cell proliferation.In addition,we found that SNHG9 promotes tumor development via regulating YAP transcriptional activation in xenograft tumor.In summary,this study found that lnc RNA SNHG9 could regulate LATS1 kinase activity and tumor progression by promoting LATS1 kinase phase separation.The discovery of the mechanism and function of SNHG9-regulated kinase phase separation may provide new intervention strategies and new targets for clinical diagnosis and treatment of tumors.