Androgen attenuates the inactivating phospho–Ser-127 modification of yes-associated protein 1 (YAP1) and promotes YAP1 nuclear abundance and activity

Abstract

The transcriptional coactivator YAP1 (yes-associated protein 1) regulates cell proliferation, cell–cell interactions, organ size, and tumorigenesis. Post-transcriptional modifications and nuclear translocation of YAP1 are crucial for its nuclear activity. The objective of this study was to elucidate the mechanism by which the steroid hormone androgen regulates YAP1 nuclear entry and functions in several human prostate cancer cell lines. We demonstrate that androgen exposure suppresses the inactivating post-translational modification phospho–Ser-127 in YAP1, coinciding with increased YAP1 nuclear accumulation and activity. Pharmacological and genetic experiments revealed that intact androgen receptor signaling is necessary for androgen's inactivating effect on phospho–Ser-127 levels and increased YAP1 nuclear entry. We also found that androgen exposure antagonizes Ser/Thr kinase 4 (STK4/MST1) signaling, stimulates the activity of protein phosphatase 2A, and thereby attenuates the phospho–Ser-127 modification and promotes YAP1 nuclear localization. Results from quantitative RT-PCR and CRISPR/Cas9–aided gene knockout experiments indicated that androgen differentially regulates YAP1-dependent gene expression. Furthermore, an unbiased computational analysis of the prostate cancer data from The Cancer Genome Atlas revealed that YAP1 and androgen receptor transcript levels correlate with each other in prostate cancer tissues. These findings indicate that androgen regulates YAP1 nuclear localization and its transcriptional activity through the androgen receptor–STK4/MST1–protein phosphatase 2A axis, which may have important implications for human diseases such as prostate cancer. The transcriptional coactivator YAP1 (yes-associated protein 1) regulates cell proliferation, cell–cell interactions, organ size, and tumorigenesis. Post-transcriptional modifications and nuclear translocation of YAP1 are crucial for its nuclear activity. The objective of this study was to elucidate the mechanism by which the steroid hormone androgen regulates YAP1 nuclear entry and functions in several human prostate cancer cell lines. We demonstrate that androgen exposure suppresses the inactivating post-translational modification phospho–Ser-127 in YAP1, coinciding with increased YAP1 nuclear accumulation and activity. Pharmacological and genetic experiments revealed that intact androgen receptor signaling is necessary for androgen's inactivating effect on phospho–Ser-127 levels and increased YAP1 nuclear entry. We also found that androgen exposure antagonizes Ser/Thr kinase 4 (STK4/MST1) signaling, stimulates the activity of protein phosphatase 2A, and thereby attenuates the phospho–Ser-127 modification and promotes YAP1 nuclear localization. Results from quantitative RT-PCR and CRISPR/Cas9–aided gene knockout experiments indicated that androgen differentially regulates YAP1-dependent gene expression. Furthermore, an unbiased computational analysis of the prostate cancer data from The Cancer Genome Atlas revealed that YAP1 and androgen receptor transcript levels correlate with each other in prostate cancer tissues. These findings indicate that androgen regulates YAP1 nuclear localization and its transcriptional activity through the androgen receptor–STK4/MST1–protein phosphatase 2A axis, which may have important implications for human diseases such as prostate cancer. YAP1 (yes-associated protein 1) and its paralog WWTR1 (WW domain–containing protein) are transcriptional coactivators (1Chen Y.A. Lu C.Y. Cheng T.Y. Pan S.H. Chen H.F. Chang N.S. WW domain–containing proteins YAP and TAZ in the Hippo pathway as key regulators in stemness maintenance, tissue homeostasis, and tumorigenesis.Front. Oncol. 2019; 9 (30805310): 6010.3389/fonc.2019.00060Crossref PubMed Scopus (51) Google Scholar, 2Ma S. Meng Z. Chen R. Guan K.L. The Hippo pathway: biology and pathophysiology.Annu. Rev. Biochem. 2019; 88 (30566373): 577-60410.1146/annurev-biochem-013118-111829Crossref PubMed Scopus (160) Google Scholar). YAP1 is a well-characterized nuclear effector of the Hippo pathway in mammals (2Ma S. Meng Z. Chen R. Guan K.L. The Hippo pathway: biology and pathophysiology.Annu. Rev. Biochem. 2019; 88 (30566373): 577-60410.1146/annurev-biochem-013118-111829Crossref PubMed Scopus (160) Google Scholar, 3Zhao B. Li L. Lei Q. Guan K.L. The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version.Genes Dev. 2010; 24 (20439427): 862-87410.1101/gad.1909210Crossref PubMed Scopus (735) Google Scholar, 4Liu A.M. Wong K.F. Jiang X. Qiao Y. Luk J.M. Regulators of mammalian Hippo pathway in cancer.Biochim. Biophys. Acta. 2012; 1826 (22683405): 357-36410.1016/j.bbcan.2012.05.006PubMed Google Scholar). The STK4/MST1, STK3/MST2, and LATS1/2 protein kinases are core components of the Hippo pathway (5Yu F.X. Guan K.L. The Hippo pathway: regulators and regulations.Genes Dev. 2013; 27 (23431053): 355-37110.1101/gad.210773.112Crossref PubMed Scopus (776) Google Scholar). YAP1 was initially identified from the protein complexes of the Src family kinases (6Sudol M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product.Oncogene. 1994; 9 (8035999): 2145-2152PubMed Google Scholar). YAP1 regulates diverse cellular activities, including cell proliferation, cell survival, cell differentiation, stem cell maintenance, cell–cell interaction, organ size, and tumorigenesis (2Ma S. Meng Z. Chen R. Guan K.L. The Hippo pathway: biology and pathophysiology.Annu. Rev. Biochem. 2019; 88 (30566373): 577-60410.1146/annurev-biochem-013118-111829Crossref PubMed Scopus (160) Google Scholar). Nuclear localization of YAP1 is critical for its transcriptional-dependent biological functions, even though a majority of YAP1 proteins are present in the cytoplasm (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar, 8Vassilev A. Kaneko K.J. Shu H. Zhao Y. DePamphilis M.L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.Genes Dev. 2001; 15 (11358867): 1229-124110.1101/gad.888601Crossref PubMed Scopus (472) Google Scholar). YAP1 exerts its transcriptional-dependent biological activity by interacting with transcription factors. The family of the TEAD transcription factors is a critical mediator of the YAP1-dependent gene transcription. Mounting evidence indicates that interaction between the YAP1 and TEAD proteins is mutual because YAP1 functions as a coactivator for TEAD-dependent gene expression (3Zhao B. Li L. Lei Q. Guan K.L. The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version.Genes Dev. 2010; 24 (20439427): 862-87410.1101/gad.1909210Crossref PubMed Scopus (735) Google Scholar, 8Vassilev A. Kaneko K.J. Shu H. Zhao Y. DePamphilis M.L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.Genes Dev. 2001; 15 (11358867): 1229-124110.1101/gad.888601Crossref PubMed Scopus (472) Google Scholar, 9Li Z. Zhao B. Wang P. Chen F. Dong Z. Yang H. Guan K.L. Xu Y. Structural insights into the YAP and TEAD complex.Genes Dev. 2010; 24 (20123905): 235-24010.1101/gad.1865810Crossref PubMed Scopus (217) Google Scholar). Although the exact mechanisms are mostly unknown, YAP1 shuttles between the cytoplasm and nucleus. Protein–protein interactions (8Vassilev A. Kaneko K.J. Shu H. Zhao Y. DePamphilis M.L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.Genes Dev. 2001; 15 (11358867): 1229-124110.1101/gad.888601Crossref PubMed Scopus (472) Google Scholar, 10Badouel C. Gardano L. Amin N. Garg A. Rosenfeld R. Le Bihan T. McNeill H. The FERM-domain protein Expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie.Dev. Cell. 2009; 16 (19289086): 411-42010.1016/j.devcel.2009.01.010Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar) and nuclear import or export signaling are possible mechanisms that control the translocations of YAP1 between the cytoplasm and nucleus (11Ege N. Dowbaj A.M. Jiang M. Howell M. Hooper S. Foster C. Jenkins R.P. Sahai E. Quantitative analysis reveals that actin and Src-family kinases regulate nuclear YAP1 and its export.Cell Syst. 2018; 6 (29909276): 692-708.e1310.1016/j.cels.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 12Kofler M. Speight P. Little D. Di Ciano-Oliveira C. Szászi K. Kapus A. Mediated nuclear import and export of TAZ and the underlying molecular requirements.Nat. 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Nuclear localization and pro-apoptotic signaling of YAP2 require intact PDZ-binding motif.Genes Cells. 2009; 14 (19371381): 607-61510.1111/j.1365-2443.2009.01292.xCrossref PubMed Scopus (54) Google Scholar). The MST1/2 and LATS1/2 kinase cascade phosphorylate Ser-127 and inactivate YAP1 (3Zhao B. Li L. Lei Q. Guan K.L. The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version.Genes Dev. 2010; 24 (20439427): 862-87410.1101/gad.1909210Crossref PubMed Scopus (735) Google Scholar, 7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar, 16Zhou D. Conrad C. Xia F. Park J.S. Payer B. Yin Y. Lauwers G.Y. Thasler W. Lee J.T. Avruch J. Bardeesy N. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.Cancer Cell. 2009; 16 (19878874): 425-43810.1016/j.ccr.2009.09.026Abstract Full Text Full Text PDF PubMed Scopus (626) Google Scholar). In addition to the covalent modification, a mechanical force could also increase YAP1 nuclear import (14Elosegui-Artola A. Andreu I. Beedle A.E.M. Lezamiz A. Uroz M. Kosmalska A.J. Oria R. Kechagia J.Z. Rico-Lastres P. Le Roux A.L. Shanahan C.M. Trepat X. Navajas D. Garcia-Manyes S. Roca-Cusachs P. Force triggers YAP nuclear entry by regulating transport across nuclear pores.Cell. 2017; 171 (29107331): 1397-1410.e1410.1016/j.cell.2017.10.008Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 17Elosegui-Artola A. Oria R. Chen Y. Kosmalska A. Pérez-Gonzalez C. Castro N. Zhu C. Trepat X. Roca-Cusachs P. Mechanical regulation of a molecular clutch defines force and in to Biol. PubMed Scopus Google Scholar). the family of and domain–containing proteins increased YAP1 nuclear import through A. H. D. proteins regulate YAP 2018; PubMed Scopus Google Scholar). TEAD or protein YAP1 nuclear localization (11Ege N. Dowbaj A.M. Jiang M. Howell M. Hooper S. Foster C. Jenkins R.P. Sahai E. Quantitative analysis reveals that actin and Src-family kinases regulate nuclear YAP1 and its export.Cell Syst. 2018; 6 (29909276): 692-708.e1310.1016/j.cels.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, C. W. nuclear of TAZ to Biol. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Meng Z. Y. J. Park Guan K.L. of Hippo pathway transcription TEAD by Biol. 2017; PubMed Scopus Google Scholar). study that androgen hormone signaling regulates the nuclear–cytoplasmic translocation of YAP1 (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google the mechanism is In this have that androgen exposure suppress the phospho–Ser-127 on YAP1, which in YAP1 protein levels and nuclear We that androgen receptor signaling was critical for the regulation of YAP1 by We also that androgen exposure the signaling and activity. data demonstrate that androgen signaling regulates the YAP1-dependent gene expression. study a mechanism of YAP1 regulation that androgen hormone cell that the of androgen on YAP1, the levels of YAP1, and AR in the prostate cancer cell We found that the levels of YAP1, and AR protein the cell and and its and WWTR1 the cell was with and The and cell YAP1, the expression of YAP1 also in the cell is the cell to study the mechanism of YAP1 regulation by androgen because an intact AR and YAP1 signaling pathway (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar). androgen signaling regulates a of YAP1 nuclear translocation (3Zhao B. Li L. Lei Q. Guan K.L. The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version.Genes Dev. 2010; 24 (20439427): 862-87410.1101/gad.1909210Crossref PubMed Scopus (735) Google Scholar, 7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar, 16Zhou D. Conrad C. Xia F. Park J.S. Payer B. Yin Y. Lauwers G.Y. Thasler W. Lee J.T. Avruch J. Bardeesy N. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.Cancer Cell. 2009; 16 (19878874): 425-43810.1016/j.ccr.2009.09.026Abstract Full Text Full Text PDF PubMed Scopus (626) Google the levels of phospho–Ser-127 and the of the YAP1 protein in and its cell to or 24 We also the levels of on YAP1 as a phospho–Ser-127 in and that androgen regulates phospho–Ser-127 on the of phospho–Ser-127 by androgen with in the of YAP1 protein S.A. Dent L.G. Kondo S. Zhao Z.W. Plachta N. Harvey K.F. Dynamic fluctuations in subcellular localization of the Hippo pathway effector Yorkie in vivo.Curr. Biol. 2018; 28 (29754899): 1651-1660.e410.1016/j.cub.2018.04.018Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, S. W. S. Y. Y. J. Lee T. B. M. H. by and its nuclear 2017; PubMed Scopus Google Scholar, B. Li L. K. Wang C.Y. 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We this cell to demonstrate androgen antagonizes signaling in a that In this the levels of phospho–Ser-127 and YAP1 protein in that to with the or was to expression. with androgen exposure which in in YAP1 protein and The Ser/Thr are to inactivate the signaling A.L. G. A. F. T. H. interaction of the mammalian Hippo pathway reveals mechanisms of 2013; 6 PubMed Scopus Google Scholar, Y. A. Wang of mammalian kinase by protein and Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, E. L. M. W. of the kinase in of by the proto-oncogene PubMed Scopus Google Scholar). a of the that androgen regulates in attenuates this the levels of phospho–Ser-127 and YAP1 protein in with control and with the of phospho–Ser-127 and YAP1 protein in the and We that a in the of YAP1 protein for its phosphorylation that increased the molecular of the YAP1 is to the inactivation of the Ser/Thr by Y. S. S. a to study the Hippo 2013; PubMed Scopus Google Scholar). with the androgen the YAP1 by the which in the on YAP1 E. L. M. W. of the kinase in of by the proto-oncogene PubMed Scopus Google Scholar, S. M. phosphatase 2A regulates signaling by and on critical Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, that androgen exposure YAP1 nuclear in with and androgen may the Ser/Thr to the activity. AR activity is necessary for the nuclear accumulation of YAP1, a analysis of AR and YAP1 proteins in with or with the androgen exposure increased the of YAP1 and AR protein in the cell the of androgen on YAP1 and AR nuclear and experiments that androgen the interaction of YAP1 with AR and the of the in the nuclear the These findings indicate that in with the of phospho–Ser-127 and of YAP1 nuclear localization by The the and the are well-characterized YAP1 P. E. J. S. Guan K.L. Li S. regulate and PubMed Scopus Google Scholar, F. M. G. L. E. B. A. S. M. 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We have also that the the of androgen on findings a mechanism of YAP1 regulation that androgen hormone data have revealed that androgen signaling phospho–Ser-127 on YAP1 in an because the of AR activity by genetic and the of phospho–Ser-127 modification by of phospho–Ser-127 in in the YAP protein and nuclear and (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar) that androgen interaction between YAP1 and AR in the cell the YAP1 and AR interaction of androgen exposure in the cell that nuclear AR and YAP1 proteins (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. 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Z. regulates YAP2 6 PubMed Scopus Google Scholar, A.L. C.Y. P. Y. of the cascade and YAP in cancer 2019; PubMed Scopus Google Scholar). Furthermore, analysis of the YAP1 indicated that was of the YAP1 the that androgen also regulates phospho–Ser-127 through the protein is with the that the protein was to the including phospho–Ser-127 on YAP1 A.J. of with signaling proteins is by the of Full Text Full Text PDF PubMed Scopus Google Scholar). the the and of YAP1 B. X. Li W. Yang Q. J. J. T. J. Li L. P. K. A. G. of YAP by the Hippo pathway is in cell and tissue growth Dev. PubMed Scopus Google Scholar). The and protein kinase signaling cascade and to the and of YAP1 through B. Li L. K. Wang C.Y. Guan K.L. phosphorylation by and regulates YAP through Dev. 2010; 24 PubMed Scopus Google Scholar). could the and transcriptional activity of YAP1 via the in Y. A. the transcriptional YAP and cell growth via phosphorylation of the of by the LATS1/2 protein 2013; PubMed Scopus Google Scholar). to demonstrate YAP1 several that other kinases and also the phosphorylation on YAP1 could also regulate YAP1 nuclear localization (3Zhao B. Li L. Lei Q. Guan K.L. The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version.Genes Dev. 2010; 24 (20439427): 862-87410.1101/gad.1909210Crossref PubMed Scopus (735) Google Scholar, S. W. S. Y. Y. J. Lee T. B. M. H. by and its nuclear 2017; PubMed Scopus Google Scholar, B. Li L. K. Wang C.Y. Guan K.L. phosphorylation by and regulates YAP through Dev. 2010; 24 PubMed Scopus Google Scholar, M. Z. Y. Chen Q. Y. insights into modifications of Hippo pathway in and PubMed Scopus Google Scholar, Meng Z. S. W. Guan K.L. phosphorylation by 2017; PubMed Scopus Google Scholar). androgen the activity of other such as Src family kinases (6Sudol M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product.Oncogene. 1994; 9 (8035999): 2145-2152PubMed Google to modulate YAP nuclear import B. Li L. K. Wang C.Y. Guan K.L. phosphorylation by and regulates YAP through Dev. 2010; 24 PubMed Scopus Google Scholar, Z. T. Park J.S. Lu W. Lu S. F. F.X. G. Guan K.L. family kinases in to MST1/2 to LATS1/2 in the Hippo Commun. 2015; 6 PubMed Scopus Google Scholar). also revealed that androgen hormone signaling regulates the YAP1-dependent gene expression. is necessary to the mechanism of androgen signaling the nuclear and transcriptional activity of YAP1 in on have a in which androgen the to phospho–Ser-127 and to YAP1 nuclear and activity. findings are crucial because androgen regulates YAP1-dependent gene expression by the interaction of YAP1 with AR and the protein are also are and because the YAP1 and AR correlate in the of prostate cancer tissues. study a mechanism of YAP1 regulation that is by the findings have important implications for human that the Hippo–YAP pathway regulates a of cellular including cell differentiation, stem cell and and in cell in and and to the cell and cell from the in The with of human YAP1 and human YAP1 or control to the of the to an of to to tissue and in a with and quantitative to the of YAP1 expression in and to the was to the The was to quantitative to the The gene expression was a K.J. of gene expression data quantitative and the 2001; PubMed Scopus Google Scholar) to the control in The in are in in in a proteins from and and phosphatase and nuclear to the B. D. S. M. is a of PubMed Scopus Google Scholar). The with an protein was with 4 as (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar). The YAP1 complexes with protein and with a proteins and by and The with and by with the to YAP1 and or AR or a and was to a (7Kuser-Abali G. Alptekin A. Lewis M. Garraway I.P. Cinar B. YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.Nat. Commun. 2015; 6 (28230103): 812610.1038/ncomms9126Crossref PubMed Scopus (44) Google Scholar). in a by with or in for The with for with for and with and in for The with the YAP1 AR or 4 The with the to or or to or for in a The with each The YAP1, or or or LATS1/2 from of or and expression was B. D. S. M. is a of PubMed Scopus Google Scholar). was into the and in the and the was as The or in to the cancer gene expression data from the data from for with prostate F. M. J. A. S. S. D. F. Q. signaling in The Cancer Genome 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). data from via the E. J. A. M.L. E. Y. B. C. N. The cancer an for cancer 2012; PubMed Scopus Google Scholar, J. G. B. Y. A. R. E. E. C. N. analysis of cancer and the 2013; 6 PubMed Scopus Google Scholar). and analysis of AR and YAP1 levels was data in the are the We and Wang for the and Amin and for quantitative The Cancer Genome Atlas protein phosphatase 2A androgen receptor knockout

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