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YAP/TAZ drives cell proliferation and tumour growth via a polyamine–eIF5A hypusination–LSD1 axis

Nature Cell Biology volume 24, pages 373–383 (2022)Cite this article

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Abstract

Metabolic reprogramming is central to oncogene-induced tumorigenesis by providing the necessary building blocks and energy sources, but how oncogenic signalling controls metabolites that play regulatory roles in driving cell proliferation and tumour growth is less understood. Here we show that oncogene YAP/TAZ promotes polyamine biosynthesis by activating the transcription of the rate-limiting enzyme ornithine decarboxylase 1. The increased polyamine levels, in turn, promote the hypusination of eukaryotic translation factor 5A (eIF5A) to support efficient translation of histone demethylase LSD1, a transcriptional repressor that mediates a bulk of YAP/TAZ-downregulated genes including tumour suppressors in YAP/TAZ-activated cells. Accentuating the importance of the YAP/TAZ–polyamine–eIF5A hypusination–LSD1 axis, inhibiting polyamine biosynthesis or LSD1 suppressed YAP/TAZ-induced cell proliferation and tumour growth. Given the frequent upregulation of YAP/TAZ activity and polyamine levels in diverse cancers, our identification of YAP/TAZ as an upstream regulator and LSD1 as a downstream effector of the oncometabolite polyamine offers a molecular framework in which oncogene-induced metabolic and epigenetic reprogramming coordinately drives tumorigenesis, and suggests potential therapeutic strategies in YAP/TAZ- or polyamine-dependent human malignancies.

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Fig. 1: YAP activation promotes polyamine biosynthesis in mouse liver.
Fig. 2: YAP/TAZ regulates ODC1 expression and polyamine biosynthesis in human HCC.
Fig. 3: Odc1 knockdown inhibits YAP-induced liver overgrowth and polyamine biosynthesis.
Fig. 4: Polyamine-mediated eIF5A hypusination (eIF5AHyp) is required for efficient translation of LSD1.
Fig. 5: LSD1 suppression inhibits YAP-induced overgrowth in mouse liver.
Fig. 6: LSD1 suppression inhibits the proliferation of human cancer cells with active YAP/TAZ.
Fig. 7: Identification and functional analysis of the putative LSD1 target genes in YAP OE mouse liver.

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Data availability

RNA-seq and ChIP-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE176329 and GSE174041. Previously published ChIP-seq and Hi-C data that were reanalysed here are available under accession numbers GSE6608153, GSE7107754 and GSE7214155. The human liver cancer data were derived from the TCGA Research Network (https://portal.gdc.cancer.gov/). The dataset derived from this resource that supports the findings of this study is available at https://www.proteinatlas.org/humanproteome/pathology/liver+cancer. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

References

  1. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Faubert, B., Solmonson, A. & De Berardinis, R. J. Metabolic reprogramming and cancer progression. Science 368, eaaw5473 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Van der Heiden, M. G. & De Berardinis, R. J. Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669 (2017).

    Article  PubMed Central  Google Scholar 

  5. Yu, F.-X., Zhao, B. & Guan, K.-L. Hippo pathway in organ size control, tissue homeostasis and cancer. Cell 163, 811–828 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP/TAZ at the roots of cancer. Cancer Cell 29, 783–803 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zheng, Y. & Pan, D. The Hippo signaling pathway in development and disease. Dev. Cell 50, 264–282 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sanchez-Vega, F. et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell 173, 321–337 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ibar, C. & Irvine, K. D. Integration of Hippo-YAP signaling with metabolism. Dev. Cell 54, 256–267 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Koo, J. H. & Guan, K. L. Interplay between YAP/TAZ and metabolism. Cell Metab. 28, 196–206 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Ardestani, A., Lupse, B. & Maedler, K. Hippo signaling: key emerging pathway in cellular and whole-body metabolism. Trends Endocrinol. Metab. 29, 492–509 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Casero, R. A. Jr, Murray Stewart, T. & Pegg, A. E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18, 681–695 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pegg, A. E. Regulation of ornithine decarboxylase. J. Biol. Chem. 281, 14529–14532 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Lee, K. P. et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size and liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 8248–8253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lu, L. et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl Acad. Sci. USA 107, 1437–1442 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhao, B. et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22, 1962–1971 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Galli, G. G. et al. YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol. Cell 60, 328–337 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, X. et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 30, 2810–2822 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Poulin, R., Lu, L., Ackermann, B., Bey, P. & Pegg, A. E. Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J. Biol. Chem. 267, 150–158 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Park, M. H., Cooper, H. L. & Folk, J. E. Identification of hypusine, an unusual amino acid, in a protein from human lymphocytes and of spermidine as its biosynthetic precursor. Proc. Natl Acad. Sci. USA 78, 2869–2873 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Abbruzzese, A., Park, M. H. & Folk, J. E. Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J. Biol. Chem. 261, 3085–3089 (1986).

    Article  CAS  PubMed  Google Scholar 

  24. Wolff, E. C., Lee, Y. B., Chung, S. I., Folk, J. E. & Park, M. H. Deoxyhypusine synthase from rat testis: purification and characterization. J. Biol. Chem. 270, 8660–8666 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Gutierrez, E. et al. eIF5A promotes translation of polyproline motifs. Mol. Cell 51, 35–45 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang, H. et al. Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol. Cell 76, 110–125 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zanconato, F. et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat. Med. 24, 1599–1610 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chang, L. et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 563, 265–269 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Qing, Y. et al. The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6. eLife 3, e02564 (2014).

    Article  PubMed Central  Google Scholar 

  30. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Maiques-Diaz, A. & Somervaille, T. C. LSD1: biologic roles and therapeutic targeting. Epigenomics 8, 1103–1116 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jakus, J., Wolff, E. C., Park, M. H. & Folk, J. E. Features of the spermidine-binding site of deoxyhypusine synthase as derived from inhibition studies. Effective inhibition by bis- and mono-guanylated diamines and polyamines. J. Biol. Chem. 268, 13151–13159 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Zhang, H. et al. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J. Biol. Chem. 284, 13355–13362 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kinnaird, A., Zhao, S., Wellen, K. E. & Michelakis, E. D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer 16, 694–707 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Kaelin, W. G. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Izzo, L. T., Affronti, H. C. & Wellen, K. E. The bidirectional relationship between cancer epigenetics and metabolism. Annu. Rev. Cancer Biol. 5, 235–257 (2021).

    Article  PubMed  Google Scholar 

  37. Gerner, E. W. & Meyskens, F. L. Jr Polyamines and cancer: old molecules, new understanding. Nat. Rev. Cancer 4, 781–792 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Arruabarrena-Aristorena, A., Zabala-Letona, A. & Carracedo, A. Oil for the cancer engine: the cross-talk between oncogenic signaling and polyamine metabolism. Sci. Adv. 4, eaar2606 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zabala-Letona, A. et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547, 109–113 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Silvera, D., Formenti, S. C. & Schneider, R. J. Translational control in cancer. Nat. Rev. Cancer 10, 254–266 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Kim, M., Kim, T., Johnson, R. L. & Lim, D. S. Transcriptional co-repressor function of the Hippo pathway transducers YAP and TAZ. Cell Rep. 11, 270–282 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Hicks-Berthet, J. et al. Yap/Taz inhibit goblet cell fate to maintain lung epithelial homeostasis. Cell Rep. 36, 109347 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee, D. H. et al. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat. Commun. 7, 11961 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Proietti, E., Rossini, S., Grohmann, U. & Mondanelli, G. Polyamines and kynurenines at the intersection of immune modulation. Trends Immunol. 41, 1037–1050 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Latour, Y. L., Gobert, A. P. & Wilson, K. T. The role of polyamines in the regulation of macrophage polarization and function. Amino Acids 52, 151–160 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    Article  PubMed  Google Scholar 

  48. Ambrosio, S., Ballabio, A. & Majello, B. Histone methyl-transferases and demethylases in the autophagy regulatory network: the emerging role of KDM1A/LSD1 demethylase. Autophagy 15, 187–196 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chong, J., Wishart, D. S. & Xia, J. Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr. Protoc. Bioinformatics 68, e86 (2019).

    Article  PubMed  Google Scholar 

  52. Forester, C. M. et al. Revealing nascent proteomics in signaling pathways and cell differentiation. Proc. Natl Acad. Sci. USA 115, 2353–2358 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zanconato, F. et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 17, 1218–1227 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chung, C. Y. et al. Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis. Cell Rep. 16, 472–486 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Takaku, M. et al. GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biol. 17, 36 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Li, D., Hsu, S., Purushotham, D., Sears, R. L. & Wang, T. WashU Epigenome Browser update 2019. Nucleic Acids Res. 47, W158–W165 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dixon, J. R. et al. Chromatin architecture reorganization during stem cell differentiation. Nature 518, 331–336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Leung, D. et al. Integrative analysis of haplotype-resolved epigenomes across human tissues. Nature 518, 350–354 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, Y. et al. The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions. Genome Biol. 19, 151 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the CRI Metabolomics Facility at UT Southwestern Medical Center for the metabolomics analysis and polyamine detection and X. Wu for assistance with CRISPR-Cas9-based gene editing. This study was supported in part by grants from the NIH (R01EY015708) and DOD (PR190360) to D.P. D.P. is an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Hongde Li, Bo-Kuan Wu, Jing Cai, Li Wang, Yonggang Zheng & Duojia Pan

  2. Eugene McDermott Center for Human Growth and Development/Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Mohammed Kanchwala & Chao Xing

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Contributions

H.L. and D.P. conceived the project. H.L. and Y.Z. designed the experiments. H.L., J.C., L.W. and B.-K.W. performed the experiments. M.K. and C.X. analysed RNA-seq and ChIP-seq data. D.P. supervised the study. H.L., Y.Z. and D.P. wrote the manuscript.

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Correspondence to Duojia Pan.

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Extended data

Extended Data Fig. 1 Metabolomics analysis of YAP OE mouse livers.

a, Schematic diagram of the experimental design. YAP is conditionally expressed in the liver by doxycycline addition. b, YAP expression levels were examined by western blot. Data are represented as mean ± s.d., n = 3 mice per group, unpaired two-tailed Student’s t-test. c, Principal component analysis (PCA) shows that YAP OE and control have different metabolic profiles. Value in the parenthesis is the proportion of variance explained by the corresponding principal component. d, Significantly up-regulated metabolites (Fold change > 1.2 and P < 0.05, unpaired two-tailed Student’s t-test) in YAP OE livers are shown as a heat map. e, Top 50 significantly down-regulated metabolites in YAP OE livers are shown as a heat map.

Source data

Extended Data Fig. 2 Sav1 knockout leads to liver overgrowth, increased levels of polyamine and ODC1 expression in mouse liver.

a, Alb-Cre mice were crossed with Sav1flox mice to knock out Sav1 (Alb-Cre;Sav1flox/flox, Sav1 KO) in the liver. Sav1flox/flox mice were used as controls. Representative liver images of one-month-old mice are shown in the left panel, and liver-to-body mass ratios are shown in the right panel. Data are represented as mean ± s.d., n = 5, unpaired two-tailed Student’s t-test. b, Levels of total polyamines in control and Sav1 KO mouse livers. Data are shown as mean ± s.e.m., n = 4, unpaired two-tailed Student’s t-test. c, Relative mRNA levels of genes involved in polyamine metabolism in control and Sav1 KO mouse livers. Data are shown as mean ± s.d., n = 4, unpaired two-tailed Student’s t-test. d,e, Relative ODC1 protein levels were examined in YAP OE and Sav1 KO mouse livers by western blot. Data are shown as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test.

Source data

Extended Data Fig. 3 YAP/TAZ regulates ODC1 transcription in human cells.

a, Relative mRNA levels of ODC1 in HPNE cells stably expressing an empty vector (control), YAP or YAPS127A were examined by RT–qPCR. Data are represented as mean ± s.d., n = 4, multiple t-test with Bonferroni correction. b, HEK293T cells were transiently transfected with empty vector or YAP5SA plasmids, and relative mRNA levels of ODC1 were measured by RT–qPCR. Data are represented as mean ± s.d., n = 4, unpaired two-tailed Student’s t-test. c, Relative mRNA levels of ODC1 in MCF10A cells transfected by lentivirus expressing an empty vector or YAP5SA were examined by RT–qPCR. Data are represented as mean ± s.d., n = 4, unpaired two-tailed Student’s t-test. d,e, MDA-MB-231 and ES-2 cells, which were reported with high YAP/TAZ activity previously, were transfected with siRNAs targeting YAP and TAZ (YAP/TAZ DKD) or non-targeting control (Ctrl). Relative mRNA levels of indicated genes were measured by RT–qPCR. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. f, ChIP-seq analysis shows potentially active enhancer regions binding with YAP/TAZ/TEAD4 in MDA-MB-231 cells. g, Hi-C data analysis shows interactive regions with ODC1 promoter in multiple human cells and liver. h, 293T cells were transiently transfected with empty vector, YAP5SA or YAP5SA/S94A plasmids, and relative mRNA levels of ODC1 were measured by RT–qPCR. Data are represented as mean ± s.d., n = 4, one-way ANOVA, Tukey’s multiple comparisons test. i, SNU-886 cells were transiently transfected with empty vector, YAP5SA or YAP5SA/S94A plasmids, and relative mRNA levels of ODC1 were measured by RT–qPCR. Data are represented as mean ± s.d., n = 4, one-way ANOVA, Tukey’s multiple comparisons test. j,k, Human HAP1 parental cells, or mutant cells deleted of #3 (E#3 M) or both #3 and #4 (E#3&4DM) TEAD-binding sites of ODC1 enhancer were transfected by empty lentivirus vector or vector expressing YAP5SA. Relative mRNA levels of ODC1 (j) and CTGF (k) were examined by RT–qPCR. Data are represented as mean ± s.d., n = 3, one-way ANOVA, Dunnett’s multiple comparisons test.

Source data

Extended Data Fig. 4 AAV-mediated ectopic expression of OAZ1 inhibits YAP-induced liver overgrowth.

a, Experimental design. One-month-old wild type (WT) and Dox inducible YAP transgenic (YAP) mice were treated with AAV8-GFP or AAV8-Alb>Oaz1. Five days later, 50 mg l-1 Dox was added in drink water to induce YAP overexpression for 10 days. b, Representative liver images of mice described in (a) and quantification of liver to body mass ratio. Data are represented as mean ± s.d., n = 5, one-way ANOVA, Dunnett’s multiple comparisons test. c, Relative Odc1 and Oaz1 mRNA levels were examined by RT–qPCR. Data are represented as mean ± s.d., n = 5, one-way ANOVA, Dunnett’s multiple comparisons test. d, Relative levels of OAZ1 and ODC1 protein were examined by western blot. Quantitation data are shown as mean ± s.d., n = 4, one-way ANOVA, Dunnett’s multiple comparisons test. e, Relative total polyamine levels were measured by a commercial kit. Data are represented as mean ± s.d., n = 5, one-way ANOVA, Dunnett’s multiple comparisons test. f, Pearson correlation between liver size and polyamine concentrations in the mice from all the three groups. n = 5 per group, r = 0.98, P < 0.0001, two-sided Pearson correlation test. g,h, Representative images of H&E and Ki67 staining of liver samples from WT, YAP and YAP + OAZ1 mice. Livers from 5 mice each experiment were examined with similar results. i, Quantitation of Ki67+ cells. Data are represented as mean ± s.d., n = 5, one-way ANOVA, Dunnett’s multiple comparisons test.

Source data

Extended Data Fig. 5 Inhibiting ODC1 impedes the proliferation of human cancer cells with active YAP/TAZ.

a,b, MDA-MB-231 and ES-2 cells were treated with PBS, 2.5 mM DFMO (ODC1 inhibitor), 1 mM putrescine or 2.5 mM DFMO plus 1 mM putrescine. Relative cell number was measured. Data are represented as mean ± s.d., n = 5, two-way ANOVA, n.s., not significant P = 0.57. c, HLE cells were treated with different concentrations of DFMO. Relative cell number was measured. Data are represented as mean ± s.d., n = 5, two-way ANOVA. d, SNU-886 cells were treated with PBS, 2.5 mM DFMO, 2.5 mM DFMO plus 1 mM putrescine. Relative cell number was measured. Data are represented as mean ± s.d., n = 6, two-way ANOVA, n.s., not significant P = 0.65. e, ODC1 knockdown efficiency was evaluated by RT–qPCR in HLE, SNU-886 and MDA-MB-231 cells two days post dox treatment. Each cell line was tested with two different doxycycline (Dox) inducible shRNAs (shODC1 #1 and shODC1 #2). Data are shown as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. f,g, HLE cells carrying shODC1 #1 or shODC1 #2 were treated with 1 μg/mL of Dox or 1 μg/mL of Dox plus 1 mM of putrescine. Relative cell number was measured. Data are represented as mean ± s.e.m., n = 6, two-way ANOVA, n.s., not significant P = 0.75. h,i, SNU-886 cells carrying shODC1 #1 or shODC1 #2 were treated with 1 μg/mL of Dox. Relative cell number was measured. Data are represented as mean ± s.d., n = 6, two-way ANOVA. j,k, MDA-MB-231 cells carrying shODC1 #1 or shODC1 #2 were treated with 1 μg/mL of Dox. Relative cell number was measured. Data are represented as mean ± s.d., n = 6, two-way ANOVA.

Source data

Extended Data Fig. 6 Identification of LSD1 as a target of eIF5AHyp.

a, Whole proteome peptide sequence analysis identified 3 enzymes directly involved in histone acetylation and methylation with polyproline motif (≥ 5 consecutive proline residues) conserved in human and mouse. b, Relative KDM6B and SETD2 protein levels in control and YAP OE livers. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. c, Relative LSD1 protein levels in control and YAP OE livers. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. d, Relative levels of H3K4me1/2 in control, YAP OE and YAP OE;Odc1 KD livers. Data are represented as mean ± s.d., n = 7, **P = 0.0046, ***P = 0.0009, one-way ANOVA with Dunnett’s multiple comparisons test. e-g, HLE, MDA-MB-231 and ES-2 cells were treated with 2.5 mM DFMO or PBS (Ctrl) for 72 hours. Relative eIF5AHyp and LSD1 levels were examined by western blot. Data are represented as mean ± s.d., n = 4, **P = 0.0019, ***P = 0.00031, unpaired two-tailed Student’s t-test. h, HLE, MDA-MB-231 and ES-2 cells were treated with 2.5 mM DFMO or PBS (Ctrl) for 72 hours. Relative LSD1 mRNA levels were examined by RT–qPCR. Data are represented as mean ± s.d., n = 3, n.s., not significant P = 0.0955, unpaired two-tailed Student’s t-test. i-k, HLE, MDA-MB-231 and ES-2 cells were treated with 10 μM GC7 or PBS (Ctrl) for 24 hours. Relative eIF5AHyp and LSD1 levels were examined by western blot. Data are represented as mean ± s.d., n = 4, *P = 0.0223, ***P = 0.0008, **unpaired two-tailed Student’s t-test. l, HLE, MDA-MB-231 and ES-2 cells were treated with 10 μM GC7 or PBS (Ctrl) for 24 hours. Relative LSD1 mRNA levels were measured by RT–qPCR. Data are represented as mean ± s.d., n = 3, n.s., not significant P = 0.112, unpaired two-tailed Student’s t-test. m-o, Western blots reveal newly synthesized LSD1 of HLE, MDA-MB-231 and ES-2 cells treated with GC7 or PBS (Ctrl) for 24 hours using the method shown in Fig. 4f. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. p-r, Mice were treated with vehicle (Control) and a single dose of 3 mg/kg TCPOBOP prepared in 10% DMSO/ 90% corn oil (TCPOBOP). Liver size (p), ODC1 protein levels (q) and LSD1 protein levels (r) were examined 7 days post TCPOBOP treatment. Data are represented as mean ± s.d., n = 5 for p, n = 3 for q and r, unpaired two-tailed Student’s t-test.

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Extended Data Fig. 7 Relative levels of individual polyamine in DFMO-treated cell lines.

a, Relative polyamine levels of AML12 cells treated with 2.5 mM DFMO or PBS (Ctrl) for 72 hours. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. b, Relative polyamine levels of HLE cells treated with 2.5 mM DFMO or PBS (Ctrl) for 72 hours. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. c, Relative polyamine levels of MDA-MB-231 cells treated with 2.5 mM DFMO or PBS (Ctrl) for 72 hours. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. d, Relative polyamine levels of ES-2 cells treated with 2.5 mM DFMO or PBS (Ctrl) for 72 hours. Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test.

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Extended Data Fig. 8 AAV-mediated Lsd1 knockout in the liver has little effect on liver size and histology in Lsd1f/f mice.

a, Wildtype (WT) and Lsd1flox/flox (Lsd1f/f) mouse livers 19 days post AAV8-ApoE/AAT1-Cre treatment, and quantification of liver to body mass ratio. Data are represented as mean ± s.d., n = 5, unpaired two-tailed Student’s t-test. b, Western blot analysis of LSD1 expression in WT and Lsd1f/f mouse livers post AAV treatment, and quantitation of relative LSD1 protein levels. Data are shown as mean ± s.d., n = 5, unpaired two-tailed Student’s t-test. c, Representative images of liver H&E staining. Livers from 5 mice each experiment were examined with similar results. d, Liver Ki67 IHC staining and quantification. Data are represented as mean ± s.d., n = 5, unpaired two-tailed Student’s t-test.

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Extended Data Fig. 9 Inhibiting LSD1 impedes the proliferation of human cancer cells with active YAP/TAZ.

a, LSD1 knockdown efficiency was evaluated by RT–qPCR in HLE, SNU-886 and MDA-MB-231 cells 2 days post doxycycline (Dox) treatment. Each cell line was tested with two different Dox inducible shRNAs (shLSD1 #1 and shLSD1 #2). Data are represented as mean ± s.d., n = 3, unpaired two-tailed Student’s t-test. b, HLE cells carrying shLSD1 #2 were treated with 1 μg/mL of Dox. Relative cell number was measured. Data are represented as mean ± s.d., n = 5, two-way ANOVA. c, SNU-886 cells carrying shLSD1 #2 were treated with 1 μg/mL of Dox. Relative cell number was measured. Data are represented as mean ± s.d., n = 6, two-way ANOVA. d, MDA-MB-231 cells carrying shLSD1 #2 were treated with 1 μg/mL of Dox. Relative cell number was measured. Data are represented as mean ± s.d., n = 6, two-way ANOVA. e, ES-2 cells were treated with different concentrations of LSD1 inhibitor SP-2577. Relative cell number was measured. Data are represented as mean ± s.d., n = 6, two-way ANOVA.

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Extended Data Fig. 10 Characterization of H3K4me1/2 ChIP-seq data in WT and YAP OE livers.

a-e, Distribution and annotation of H3K4me1/2 ChIP peaks in WT and YAP OE liver samples. f, Overlap of genes annotated with decreased H3K4me1 and H3K4me2 ChIP peak signal in YAP OE livers (Hypergeometric test, P < 1.00e-200).

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41556_2022_848_MOESM3_ESM.xlsx

Supplementary Tables 1–6 Supplementary Table 1 Correlations between YAP/TAZ and ODC1 mRNA levels in multiple cancer types. Supplementary Table 2 RNA-seq analysis of livers of WT, YAP OE and YAP OE;Lsd1 KO mice. Supplementary Table 3 Annotation of H3K4me1 ChIP peaks with decreased enrichment levels in YAP OE liver samples. Supplementary Table 4 Annotation of H3K4me2 ChIP peaks with decreased enrichment levels in YAP OE liver samples. Supplementary Table 5 Primers used for RT–qPCR. Supplementary Table 6 The sequence of mutated ODC1 enhancer #3 and #4 of HAP1 cells.

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Li, H., Wu, BK., Kanchwala, M. et al. YAP/TAZ drives cell proliferation and tumour growth via a polyamine–eIF5A hypusination–LSD1 axis. Nat Cell Biol 24, 373–383 (2022). https://doi.org/10.1038/s41556-022-00848-5

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