Regulation Of Telomerase Catalytic Subunit HTERT Expresson By Hippo Pathway

As a reverse transcriptase which synthesizes telomere DNA,telomerase maintains telomere length and genomic stability,and is closely related to cell senescence and tumorigenesis.However,the mechanisms governing telomerase reactivation in cancer remain incompletely understood.Hippo signaling pathway which is mainly composed by the kinase cascade of MST1/2 and LATS1/2 in mammals,regulates gene expression by phosphorylating and inhibiting the transcriptional coactivators YAP and TAZ,and plays an important role in the regulation of organ size,tissue regeneration,and tumor development.Recent studies have found that LPA can inhibit the Hippo pathway kinase LATS1/2 and promote the activation of YAP.Early studies in our laboratory found that serum lysophosphatidic acid LPA can induce the expression of telomerase catalytic subunits hTERT and telomerase activity,but the mechanism has not been studied.This indicates that Hippo signaling pathway is involved in the regulation of hTERT.We found that when cells were treated with LPA,Hippo signaling pathway was inhibited and YAP was dephosphorylated and nuclear localized,resulting in elevation of hTERT mRNA and protein expression levels.Transfection of YAP-WT and YAP-activated mutants,knockout of YAP upstream kinase LATS1/2,both can upregulate hTERT mRNA and protein expression.Conversely,knockdown of YAP in LATS1/2 knockout cells reduced hTERT expression levels.Dual-Luciferase Reporter Assay showed that binding of YAP with the transcription factor TEAD can activate the promoter activity of hTERT,and the potential binding site on hTERT promoter was identified,which is further verified by chromosomal co-immunoprecipitation.Taken together,our study indicates that YAP can activate the expression of hTERT by regulating its promoter activity,contributing to further explore the biological significance of the regulation of telomerase activity by Hippo signaling pathway.