Study On The Transrepression Of COX-2 By Hippo Effectors YAP/TAZ

COX-2,the rate-limiting enzyme for the conversion of arachidonic acid into prostaglandin,is involved in many physiological and pathological processes such as inflammatory response and angiogenesis.COX-2 has also been implicated in various diseases such as osteoarthritis,Alzheimer's disease,cardiovascular risk and neoplasia.The expression of COX-2 is inducible mostly at the transcription level by diverse intra-and extracellular stimuli,including growth factors,pro-inflammatory factors and tumor-promoting agents.However,whether microenvironmetal cues such as mechanical stress could modulate the induction of COX-2 is still elusive.Here,we discovered that cell density could regulate the induction of COX-2 by diverse stimuli such as pro-inflammatory cytokines,hypoxia and starvation.This regulation is achieved through Hippo signaling,an important pathway involved in the organ size control and tissue homeostasis that is regulated by different mechanical cues like cell density,geometry and stiffness of extracellular matrix.Our study demonstrates that low cell density inactivates Hippo pathway,the transcription of COX-2 is repressed by co-transcriptional factors YAP and TAZ,the downstream effectors of Hippo signaling.Conversely,high cell density leads to the activation of Hippo pathway,which results in the restriction of YAP/TAZ in the cytosol and the enhancement of COX-2 induction.The transcriptional factors TEADs are also required for the repression of COX-2 by YAP/TAZ.Mechanistically,HDAC7 specifically forms complex with YAP/TAZ and TEADs and binds directly to the promoter region of COX-2 to silence its transcription.Functionally,the presence of YAP in the nucleus impairs the ability of migration and invasion in human non-small cell lung cancer cell line H358 in vitro,whereas overexpression of COX-2 could strongly rescue this process,which indicates the suppression of COX-2 expression is critical for antagonistic action of YAP/TAZ on cancer cell metastasis.Microarray anlysis also shows Hippo pathway tightly regulates various cellular functions including cell spreading,migration and angiogenesis,among which,most related genes are downregulated by active YAP.Our findings connect extra-cellular physical cues with inner inflammation response,and provide a broader insight into the transrepression function of YAP/TAZ.