Preliminary Study On Roles Of YAP Arginine Methylation In The Hippo Pathway And Cancer Cell Proliferation

The Hippo pathway plays a crucial role in regulating cell survival,organ size and tissue homeostasis.Dysregulation of this pathway leads to tumorigenesis.The mjorcomponents in the Hippo pathway include mammalian ste20-like protein kinase 1/2(MST1/2),large tumor suppressor 1/2(LATS1/2),and yes-associated protein(YAP),transcriptional coactivator with pdz-binding motif(TAZ)and other regulatory proteins.YAP functions as a key effector protein in the Hippo pathway.Post-translationmodification of YAP plays a key role in controlling Hippo-YAP pathway activation and tumorigenesis.For example,YAP serine 127(S127)phosphorylation and YAP serine 109(S109)are involved in regulating the nuclear translocation and downstream target gene transcription.But so far,there is very little discussion about YAP methylationmodification.Arginine methylation is a common post-translational modification of proteins in eukaryotes,and its substrates include histones and non-histone proteins.Arginine methylation is catalyzed by evolutionarily conserved Protein ArginineMethyltransferases(PRMTs).There are three main forms of methylarginines identified in eukaryotes:?-N~G-monomethylarginine(MMA),?-N~G,N~G-asymmetricdimethylarginine(a DMA),and?-N~G,N~G-symmetric dimethylarginine(s DMA).Agrowing number of studies have found that abnormal methylation of arginine is closely related to many tumors.However,it is unclear whether there is arginine methylation in YAP protein.In this study,we confirmed that YAP was methylated at Arginine 124(R124)at the molecular level,which is regulated by the energy status of the cell,such as glucose concentration.To explore YAP R124 methylation regulate mechanism of Hippo pathwa y,we found YAP R124 methylation inhibits YAP S127 phosphorylation.YAP S127phosphorylation is the key to control nuclear translocation and downstream target gene transcription,we further found YAP R124 methylation promotes YAP into the nucleus and downstream target gene transcription;Previous studies have proved that YAP is an oncogene in lung cancer.Compared with normal tissues,YAP has been detected to be diffuse and overexpressed in nucleus in human lung cancer tissues.But how YAPperforms its carcinogenic functions is unclear.Therefore,we demonstrated that YAP R124 methylation promoted cell proliferation and colony formation of non-small cell lung cancer(NSCLC)cells at the cellular level.In summary,we found that YAP R124methylation regulates Hippo pathway by influencing YAP S127 phosphorylation.Moreover,YAP arginine methylation can play its physiological function of promoting the proliferation of cancer cells through the Hippo pathway in NSCLC cells,In this paper,the effect of YAP arginine methylation on Hippo pathway regulation andNSCLC cell proliferation was preliminarily discussed,and The important new mechan-ism of the regulation of Hippo pathway by arginine methylation modification wasdiscovered,which provides a new way to further explore the molecular mechanism of YAP arginine methylation modification and the treatment of diseases.