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.

  • Original Article
  • Published:

HSF1 regulation of β-catenin in mammary cancer cells through control of HuR/elavL1 expression

Oncogene volume 34, pages 2178–2188 (2015)Cite this article

Subjects

Abstract

There is now compelling evidence to indicate a place for heat shock factor 1 (HSF1) in mammary carcinogenesis, tumour progression and metastasis. Here we have investigated a role for HSF1 in regulating the expression of the stem cell renewal factor β-catenin in immortalized human mammary epithelial and carcinoma cells. We found HSF1 to be involved in regulating the translation of β-catenin, by investigating effects of gain and loss of HSF1 on this protein. Interestingly, although HSF1 is a potent transcription factor, it was not directly involved in regulating levels of β-catenin mRNA. Instead, our data suggest a complex role in translational regulation. HSF1 was shown to regulate levels of the RNA-binding protein HuR that controlled β-catenin translation. An extra complexity was added to this scenario when it was shown that the long non-coding RNA molecule lincRNA-p21, known to be involved in β-catenin mRNA (CTNNB1) translational regulation, was controlled by HSF1 repression. We have shown previously that HSF1 was positively regulated through phosphorylation by mammalian target of rapamycin (mTOR) kinase on a key residue, serine 326, essential for transcriptional activity. In this study, we found that mTOR knockdown not only decreased HSF1-S326 phosphorylation in mammary cells, but also decreased β-catenin expression through a mechanism requiring HuR. Our data point to a complex role for HSF1 in the regulation of HuR and β-catenin expression that may be significant in mammary carcinogenesis.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Ciocca DR, Arrigo AP, Calderwood SK . Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 2013; 87: 19–48.

    Article  CAS  Google Scholar 

  2. Calderwood SK, Gong J . Molecular chaperones in mammary cancer growth and breast tumor therapy. J Cell Biochem 2011; 113: 1096–1103.

    Article  Google Scholar 

  3. Min JN, Huang L, Zimonjic DB, Moskophidis D, Mivechi NF . Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors. Oncogene 2007; 26: 5086–5097.

    Article  CAS  Google Scholar 

  4. Jin X, Moskophidis D, Mivechi NF . Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab 2011; 14: 91–103.

    Article  CAS  Google Scholar 

  5. Calderwood SK . HSF1, a versatile factor in tumorogenesis. Curr Mol Med 2012; 12: 1102–1107.

    Article  CAS  Google Scholar 

  6. Ciocca DR, Calderwood SK . Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 2005; 10: 86–103.

    Article  CAS  Google Scholar 

  7. Dai C, Whitesell L, Rogers AB, Lindquist S . Heat shock factor 1 is a powerful multifaceted modifier of carcinogenisis. Cell 2007; 130: 1005–1018.

    Article  CAS  Google Scholar 

  8. Khaleque MA, Bharti A, Sawyer D, Gong J, Benjamin IJ, Stevenson MA et al. Induction of heat shock proteins by heregulin beta1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 2005; 24: 6564–6573.

    Article  CAS  Google Scholar 

  9. Khaleque MA, Bharti A, Gong J, Gray PJ, Sachdev V, Ciocca DR et al. Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1. Oncogene 2008; 27: 1886–1893.

    Article  CAS  Google Scholar 

  10. Chou SD, Prince T, Gong J, Calderwood SK . mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS ONE 2012; 7: e39679.

    Article  CAS  Google Scholar 

  11. Zhang Y, Murshid A, Prince T, Calderwood SK . Protein kinase A regulates molecular chaperone transcription and protein aggregation. PLoS ONE 2011; 6: e28950.

    Article  CAS  Google Scholar 

  12. Murshid A, Chou SD, Prince T, Zhang Y, Bharti A, Calderwood SK . Protein kinase A binds and activates heat shock factor 1. PLoS ONE 2010; 5: e13830.

    Article  Google Scholar 

  13. Wang X, Grammatikakis N, Siganou A, Stevenson MA, Calderwood SK . Interactions between extracellular signal-regulated protein kinase 1, 14-3-3epsilon, and heat shock factor 1 during stress. J Biol Chem 2004; 279: 49460–49469.

    Article  CAS  Google Scholar 

  14. Wang X, Grammatikakis N, Siganou A, Calderwood SK . Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3 epsilon binding, and cytoplasmic sequestration of heat shock factor 1. Mol Cell Biol 2003; 23: 6013–6026.

    Article  CAS  Google Scholar 

  15. Chu B, Soncin F, Price BD, Stevenson MA, Calderwood SK . Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J Biol Chem 1996; 271: 30847–30857.

    Article  CAS  Google Scholar 

  16. Kline MP, Morimoto RI . Repression of the heat shock factor1 transcriptional activation domain is modulated by constitutive phosphorylation. Mol Cell Biol 1997; 17: 2107–2115.

    Article  CAS  Google Scholar 

  17. Knauf U, Newton EM, Kyriakis J, Kingston RE . Repression of heat shock factor 1 activity at control temperature by phosphorylation. Genes Dev 1996; 10: 2782–2793.

    Article  CAS  Google Scholar 

  18. Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI et al. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol Cell Biol 2003; 23: 2953–2968.

    Article  CAS  Google Scholar 

  19. Chu B, Zhong R, Soncin F, Stevenson MA, Calderwood SK . Transcriptional activity of heat shock factor 1 at 37 degrees C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Calpha and Czeta. J Biol Chem 1998; 273: 18640–18646.

    Article  CAS  Google Scholar 

  20. Ma XM, Blenis J . Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009; 10: 307–318.

    Article  Google Scholar 

  21. Yecies JL, Manning BD . mTOR links oncogenic signaling to tumor cell metabolism. J Mol Med 2011; 89: 221–228.

    Article  CAS  Google Scholar 

  22. MacDonald BT, Tamai K, He X . Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17: 9–26.

    Article  CAS  Google Scholar 

  23. Kemler R . From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet 1993; 9: 317–321.

    Article  CAS  Google Scholar 

  24. Vleminckx K, Kemler R, Hecht A . The C-terminal transactivation domain of beta-catenin is necessary and sufficient for signaling by the LEF-1/beta-catenin complex in Xenopus laevis. Mech Dev 1999; 81: 65–74.

    Article  CAS  Google Scholar 

  25. Gotoh J, Obata M, Yoshie M, Kasai S, Ogawa K . Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. Carcinogenesis 2003; 24: 435–442.

    Article  CAS  Google Scholar 

  26. Metcalfe C, Bienz M . Inhibition of GSK3 by Wnt signalling—two contrasting models. J Cell Sci 2011; 124 (Pt 21): 3537–3544.

    Article  CAS  Google Scholar 

  27. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al. COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 2011; 39 (Database issue): D945–D950.

    Article  CAS  Google Scholar 

  28. Charafe-Jauffret E, Ginestier C, Birnbaum D . Breast cancer stem cells: tools and models to rely on. BMC Cancer 2009; 9: 202.

    Article  Google Scholar 

  29. Santagata S, Hu R, Lin NU, Mendillo ML, Collins LC, Hankinson SE et al. High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci USA 2011; 108: 18378–18383.

    Article  CAS  Google Scholar 

  30. Lindvall C, Bu W, Williams BO, Li Y . Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev 2007; 3: 157–168.

    Article  CAS  Google Scholar 

  31. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409–414.

    Article  CAS  Google Scholar 

  32. Veronese A, Visone R, Consiglio J, Acunzo M, Lupini L, Kim T et al. Mutated beta-catenin evades a microRNA-dependent regulatory loop. Proc Natl Acad Sci USA 2010; 108: 4840–4845.

    Article  Google Scholar 

  33. Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 2010; 12: 247–256.

    Article  CAS  Google Scholar 

  34. Saydam O, Shen Y, Wurdinger T, Senol O, Boke E, James MF et al. Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway. Mol Cell Biol 2009; 29: 5923–5940.

    Article  CAS  Google Scholar 

  35. Su J, Zhang A, Shi Z, Ma F, Pu P, Wang T et al. MicroRNA-200a suppresses the Wnt/beta-catenin signaling pathway by interacting with beta-catenin. Int J Oncol 2012; 40: 1162–1170.

    CAS  PubMed  Google Scholar 

  36. Srikantan S, Gorospe M . HuR function in disease. Front Biosci 2012; 17: 189–205.

    Article  CAS  Google Scholar 

  37. Nabors LB, Gillespie GY, Harkins L, King PH . HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res 2001; 61: 2154–2161.

    CAS  Google Scholar 

  38. Dixon DA, Tolley ND, King PH, Nabors LB, McIntyre TM, Zimmerman GA et al. Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. J Clin Invest 2001; 108: 1657–1665.

    Article  CAS  Google Scholar 

  39. Barreau C, Paillard L, Osborne HB . AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res 2005; 33: 7138–7150.

    Article  CAS  Google Scholar 

  40. Lebedeva S, Jens M, Theil K, Schwanhausser B, Selbach M, Landthaler M et al. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol Cell 2011; 43: 340–352.

    Article  CAS  Google Scholar 

  41. Lopez de Silanes I, Fan J, Yang X, Zonderman AB, Potapova O, Pizer ES et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene 2003; 22: 7146–7154.

    Article  CAS  Google Scholar 

  42. Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S et al. LincRNA-p21 suppresses target mRNA translation. Mol Cell 2012; 47: 648–655.

    Article  CAS  Google Scholar 

  43. Gabai VL, Meng L, Kim G, Mills TA, Benjamin IJ, Sherman MY . Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR. Mol Cell Biol 2012; 32: 929–940.

    Article  CAS  Google Scholar 

  44. Kim G, Meriin AB, Gabai VL, Christians E, Benjamin I, Wilson A et al. The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype. Aging Cell 2012; 11: 617–627.

    Article  CAS  Google Scholar 

  45. Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, Tamimi RM et al. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 2012; 150: 549–562.

    Article  CAS  Google Scholar 

  46. Santagata S, Mendillo ML, Tang YC, Subramanian A, Perley CC, Roche SP et al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 2013; 341: 1238303.

    Article  Google Scholar 

  47. Weng D, Penzner JH, Song B, Koido S, Calderwood SK, Gong J . Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers. Breast Cancer Res 2012; 14: R18.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Department of Radiation Oncology, Beth Israel Deaconess Medical Center for support and encouragement. We are very grateful for help with construct preparation from Dr Tom Prince. This work was supported by NIH research grants RO-1CA047407, R01CA119045 and RO-1CA094397.

Author information

Author notes

  1. S-D Chou and A Murshid: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA

    S-D Chou, A Murshid, T Eguchi & S K Calderwood

  2. Boston University Medical Center, Boston, MA, USA

    J Gong

Authors
  1. S-D Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Murshid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S K Calderwood
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S K Calderwood.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chou, SD., Murshid, A., Eguchi, T. et al. HSF1 regulation of β-catenin in mammary cancer cells through control of HuR/elavL1 expression. Oncogene 34, 2178–2188 (2015). https://doi.org/10.1038/onc.2014.177

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.177

Search

Advanced search

Quick links