Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A novel regulator of ER Ca2+ drives Hippo-mediated tumorigenesis

Oncogene volume 39, pages 1378–1387 (2020)Cite this article

Subjects

Abstract

Calcium ion (Ca2+) is a versatile second messenger that regulates various cellular and physiological functions. However, the in vivo molecular mechanisms by which Ca2+ alterations contribute to tumor growth remain poorly explored. Here we show that Emei is a novel ER Ca2+ regulator that synergizes with RasV12 to induce tumor growth via JNK-mediated Hippo signaling. Emei disruption reduces ER Ca2+ level and subsequently leads to JNK activation and Hippo inactivation. Importantly, genetically increasing cytosolic Ca2+ concentration cooperates with RasV12 to drive tumor growth via inactivating the Hippo pathway. Finally, we identify POSH as a crucial link that bridges cytosolic Ca2+ alteration with JNK activation and Hippo-mediated tumor growth. Together, our findings provide a novel mechanism of tumor growth that acts through intracellular Ca2+ levels to modulate JNK-mediated Hippo signaling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Roderick HL, Cook SJ. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer. 2008;8:361–75.

    CAS  PubMed  Google Scholar 

  2. Giorgi C, Danese A, Missiroli S, Patergnani S, Pinton P. Calcium dynamics as a machine for decoding signals. Trends Cell Biol. 2018;28:258–73.

    CAS  PubMed  Google Scholar 

  3. Monteith GR, Prevarskaya N, Roberts-Thomson SJ. The calcium-cancer signalling nexus. Nat Rev Cancer. 2017;17:367–80.

    CAS  PubMed  Google Scholar 

  4. Bustos G, Cruz P, Lovy A, Cardenas C. Endoplasmic reticulum-mitochondria calcium communication and the regulation of mitochondrial metabolism in cancer: a novel potential target. Front Oncol. 2017;7:199.

    PubMed  PubMed Central  Google Scholar 

  5. Feng M, Grice DM, Faddy HM, Nguyen N, Leitch S, Wang Y, et al. Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell. 2010;143:84–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Prasad V, Boivin GP, Miller ML, Liu LH, Erwin CR, Warner BW, et al. Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility. Cancer Res. 2005;65:8655–61.

    CAS  PubMed  Google Scholar 

  7. Zhu H, Zhang H, Jin F, Fang M, Huang M, Yang CS, et al. Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma. Oncotarget. 2014;5:3455–71.

    PubMed  PubMed Central  Google Scholar 

  8. McAndrew D, Grice DM, Peters AA, Davis FM, Stewart T, Rice M, et al. ORAI1-mediated calcium influx in lactation and in breast cancer. Mol Cancer Ther. 2011;10:448–60.

    CAS  PubMed  Google Scholar 

  9. Shibao K, Fiedler MJ, Nagata J, Minagawa N, Hirata K, Nakayama Y, et al. The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma. Cell Calcium. 2010;48:315–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Enomoto M, Siow C, Igaki T. Drosophila as a cancer model. Adv Exp Med Biol. 2018;1076:173–94.

    CAS  PubMed  Google Scholar 

  11. Mirzoyan Z, Sollazzo M, Allocca M, Valenza AM, Grifoni D, Bellosta P. Drosophila melanogaster: a model organism to study cancer. Front Genet. 2019;10:51.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu T, Wang W, Zhang S, Stewart RA, Yu W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development. 1995;121:1053–63.

    CAS  PubMed  Google Scholar 

  13. Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell. 2005;122:421–34.

    CAS  PubMed  Google Scholar 

  14. Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 1995;9:534–46.

    CAS  PubMed  Google Scholar 

  15. Pantalacci S, Tapon N, Leopold P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol. 2003;5:921–7.

    CAS  PubMed  Google Scholar 

  16. Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 2003;5:914–20.

    CAS  PubMed  Google Scholar 

  17. Wu S, Huang J, Dong J, Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003;114:445–56.

    CAS  PubMed  Google Scholar 

  18. Lee T, Luo L. Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 2001;24:251–4.

    CAS  PubMed  Google Scholar 

  19. Pagliarini RA, Xu T. A genetic screen in Drosophila for metastatic behavior. Science. 2003;302:1227–31.

    CAS  PubMed  Google Scholar 

  20. Ma X, Lu JY, Dong Y, Li D, Malagon JN, Xu T. PP6 Disruption synergizes with oncogenic Ras to promote JNK-dependent tumor growth and invasion. Cell Rep. 2017;19:2657–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu M, Pastor-Pareja JC, Xu T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature. 2010;463:545–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pan D. Hippo signaling in organ size control. Genes Dev. 2007;21:886–97.

    CAS  PubMed  Google Scholar 

  23. Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–52.

    CAS  PubMed  Google Scholar 

  25. Moreno E, Yan M, Basler K. Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol. 2002;12:1263–8.

    CAS  PubMed  Google Scholar 

  26. Igaki T, Kanda H, Yamamoto-Goto Y, Kanuka H, Kuranaga E, Aigaki T, et al. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 2002;21:3009–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ma X, Li W, Yu H, Yang Y, Li M, Xue L, et al. Bendless modulates JNK-mediated cell death and migration in Drosophila. Cell Death Differ. 2014;21:407–15.

    CAS  PubMed  Google Scholar 

  28. Ma X, Chen Y, Zhang S, Xu W, Shao Y, Yang Y. Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila. Oncogene. 2016;35:846–55.

    CAS  PubMed  Google Scholar 

  29. Igaki T, Pagliarini RA, Xu T. Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol. 2006;16:1139–46.

    CAS  PubMed  Google Scholar 

  30. Uhlirova M, Bohmann D. JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 2006;25:5294–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ma X, Chen Y, Xu W, Wu N, Li M, Cao Y, et al. Impaired Hippo signaling promotes Rho1-JNK-dependent growth. Proc Natl Acad Sci USA. 2015;112:1065–70.

    CAS  PubMed  Google Scholar 

  32. Ma X, Wang H, Ji J, Xu W, Sun Y, Li W, et al. Hippo signaling promotes JNK-dependent cell migration. Proc Natl Acad Sci USA. 2017;114:1934–9.

    CAS  PubMed  Google Scholar 

  33. Ohsawa S, Sato Y, Enomoto M, Nakamura M, Betsumiya A, Igaki T. Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature. 2012;490:547–51.

    CAS  PubMed  Google Scholar 

  34. Ohsawa S, Takemoto D, Igaki T. Dissecting tumour heterogeneity in flies: genetic basis of interclonal oncogenic cooperation. J Biochem. 2014;156:129–36.

    CAS  PubMed  Google Scholar 

  35. Cong B, Ohsawa S, Igaki T. JNK and Yorkie drive tumor progression by generating polyploid giant cells in Drosophila. Oncogene. 2018;37:3088–97.

    CAS  PubMed  Google Scholar 

  36. Sun G, Irvine KD. Ajuba family proteins link JNK to Hippo signaling. Sci Signal. 2013;6:ra81.

    PubMed  Google Scholar 

  37. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15:642–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ziosi M, Baena-Lopez LA, Grifoni D, Froldi F, Pession A, Garoia F, et al. dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLoS Genet. 2010;6:e1001140.

    PubMed  PubMed Central  Google Scholar 

  39. Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD. Delineation of a Fat tumor suppressor pathway. Nat Genet. 2006;38:1142–50.

    CAS  PubMed  Google Scholar 

  40. Neto-Silva RM, de Beco S, Johnston LA. Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. Dev Cell. 2010;19:507–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C, et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2006;8:27–36.

    CAS  PubMed  Google Scholar 

  42. Oh H, Irvine KD. In vivo regulation of Yorkie phosphorylation and localization. Development. 2008;135:1081–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ma X, Huang J, Tian Y, Chen Y, Yang Y, Zhang X, et al. Myc suppresses tumor invasion and cell migration by inhibiting JNK signaling. Oncogene. 2017;36:3159–67.

    CAS  PubMed  Google Scholar 

  44. Srivastava A, Pastor-Pareja JC, Igaki T, Pagliarini R, Xu T. Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion. Proc Natl Acad Sci USA. 2007;104:2721–6.

    CAS  PubMed  Google Scholar 

  45. McEwen DG, Peifer M. Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. Development. 2005;132:3935–46.

    CAS  PubMed  Google Scholar 

  46. Groenendyk J, Agellon LB, Michalak M. Coping with endoplasmic reticulum stress in the cardiovascular system. Annu Rev Physiol. 2013;75:49–67.

    CAS  PubMed  Google Scholar 

  47. Ryoo HD, Domingos PM, Kang MJ, Steller H. Unfolded protein response in a Drosophila model for retinal degeneration. EMBO J. 2007;26:242–52.

    CAS  PubMed  Google Scholar 

  48. Ma X, Guo X, Richardson HE, Xu T, Xue L. POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation. Proc Natl Acad Sci USA. 2018;115:2150–5.

    CAS  PubMed  Google Scholar 

  49. Kukekov NV, Xu Z, Greene LA. Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic activation of JNKs. J Biol Chem. 2006;281:15517–24.

    CAS  PubMed  Google Scholar 

  50. Tsuda M, Seong KH, Aigaki T. POSH, a scaffold protein for JNK signaling, binds to ALG-2 and ALIX in Drosophila. FEBS Lett. 2006;580:3296–3300.

    CAS  PubMed  Google Scholar 

  51. Xu Z, Kukekov NV, Greene LA. POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J. 2003;22:252–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu Z, Kukekov NV, Greene LA. Regulation of apoptotic c-Jun N-terminal kinase signaling by a stabilization-based feed-forward loop. Mol Cell Biol. 2005;25:9949–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tuvia S, Taglicht D, Erez O, Alroy I, Alchanati I, Bicoviski V, et al. The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp. J Cell Biol. 2007;177:51–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Moraru A, Cakan-Akdogan G, Strassburger K, Males M, Mueller S, Jabs M, et al. THADA regulates the organismal balance between energy storage and heat production. Dev Cell. 2017;41:450.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are thankful for Bloomington, VDRC and DGRC stock centers for providing fly stocks, Lei Xue for comments. This research was supported in part by Natural Science Foundation of China Grants 31601024 to XM. Work in the Xu lab was supported by NIH grant R01CA069408. J-Y Lu was supported by American Cancer Society, and NCI-NRSA (F32CA132311) postdoctoral fellowships. XM and TX are supported by Westlake University.

Author information

Author notes

  1. Jin-Yu Lu

    Present address: Baylor College of Medicine, Hematology & Oncology, Houston, TX, USA

Authors and Affiliations

  1. School of Life Sciences, Westlake University, Hangzhou, China

    Xianjue Ma, Jinan Fang, Yue Qiu, Peng Liu & Tian Xu

  2. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    Xianjue Ma, Jin-Yu Lu & Tian Xu

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Alexandra Moraru & Aurelio A. Teleman

  4. Heidelberg University, 69120, Heidelberg, Germany

    Aurelio A. Teleman

  5. CellNetworks - Cluster of Excellence, Heidelberg University, Heidelberg, Germany

    Aurelio A. Teleman

Authors
  1. Xianjue Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Yu Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandra Moraru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aurelio A. Teleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinan Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yue Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XM, JL, and TX conceived the study. JL performed the genetic screen, identified and characterized Emei, and analyzed data. AM and AT performed ER calcium analysis experiments and analyzed data. JF, YQ, and PL performed experiments for revised paper. XM performed the rest experiments, analyzed data and wrote the paper.

Corresponding authors

Correspondence to Xianjue Ma or Tian Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, X., Lu, JY., Moraru, A. et al. A novel regulator of ER Ca2+ drives Hippo-mediated tumorigenesis. Oncogene 39, 1378–1387 (2020). https://doi.org/10.1038/s41388-019-1076-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-1076-z

This article is cited by

Search

Advanced search

Quick links