Tumor Biology

, Volume 36, Issue 7, pp 4923–4931 | Cite as

Multifaceted roles of HSF1 in cancer

  • Sufang Jiang
  • Kailing Tu
  • Qiang Fu
  • David C. Schmitt
  • Lan Zhou
  • Na Lu
  • Yuhua Zhao


Heat shock transcription factor 1 (HSF1) is the master regulator of the heat shock response. Accumulating evidence shows that HSF1 is overexpressed in a variety of human cancers, is associated with cancer aggressiveness, and could serve as an independent diagnostic or prognostic biomarker. In this review, we will provide an overview of the multifaceted roles of HSF1 in cancer, with a special focus on the four underlying molecular mechanisms involved. First, HSF1 regulates the expression of heat shock proteins (HSPs) including HSP90, HSP70, and HSP27. Second, HSF1 regulates cellular metabolism, including glycolysis and lipid metabolism. Third, HSF1 serves as a regulator of different signaling pathways, such as HuR-HIF-1, Slug, protein kinase C (PKC), nuclear factor-kappaB (NF-κB), PI3K-AKT-mTOR, and mitogen-activated protein kinase (MAPK) pathways. Finally, HSF1 regulates microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Overall, HSF1 plays many important roles in cancer via regulating cell proliferation, anti-apoptosis, epithelial-mesenchymal transition (EMT), migration, invasion, and metastasis and may be a potential therapeutic target for human cancers.


HSF1 HSPs Metabolism Signaling pathways Cancer 



The authors thank Dr. Ming Tan (Mitchell Cancer Institute, University of South Alabama) for helping to revise our manuscript. The authors acknowledge financial support for the projects supported by National Natural Sciences Foundation of China (81272907, J1103604) and the project 2012-1707-7-7 sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.


  1. 1.
    Pirkkala L, Nykanen P, Sistonen L. Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. FASEB J. 2001;15:1118–31.CrossRefPubMedGoogle Scholar
  2. 2.
    Sorger PK. Heat shock factor and the heat shock response. Cell. 1991;65:363–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Westerheide SD, Morimoto RI. Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem. 2005;280:33097–100.CrossRefPubMedGoogle Scholar
  4. 4.
    Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005;5:761–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Chuma M, Sakamoto N, Nakai A, Hige S, Nakanishi M, Natsuizaka M, et al. Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-kappaB/mitogen-activated protein kinase. Carcinogenesis. 2014;35:272–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Fang F, Chang R, Yang L. Heat shock factor 1 promotes invasion and metastasis of hepatocellular carcinoma in vitro and in vivo. Cancer. 2012;118:1782–94.CrossRefPubMedGoogle Scholar
  7. 7.
    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 U S A. 2011;108:18378–83.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Engerud H, Tangen IL, Berg A, Kusonmano K, Halle MK, Oyan AM, et al. High level of HSF1 associates with aggressive endometrial carcinoma and suggests potential for HSP90 inhibitors. Br J Cancer. 2014;111:78–84.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ishiwata J, Kasamatsu A, Sakuma K, Iyoda M, Yamatoji M, Usukura K, et al. State of heat shock factor 1 expression as a putative diagnostic marker for oral squamous cell carcinoma. Int J Oncol. 2012;40:47–52.PubMedGoogle Scholar
  10. 10.
    Hoang AT, Huang J, Rudra-Ganguly N, Zheng J, Powell WC, Rabindran SK, et al. A novel association between the human heat shock transcription factor 1 (HSF1) and prostate adenocarcinoma. Am J Pathol. 2000;156:857–64.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cen H, Zheng S, Fang YM, Tang XP, Dong Q. Induction of HSF1 expression is associated with sporadic colorectal cancer. World J Gastroenterol. 2004;10:3122–6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell. 2014;158:564–78.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Dai C, Whitesell L, Rogers AB, Lindquist S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell. 2007;130:1005–18.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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;32:929–40.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Xi C, Hu Y, Buckhaults P, Moskophidis D, Mivechi NF. Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. J Biol Chem. 2012;287:35646–57.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Meng L, Gabai VL, Sherman MY. Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis. Oncogene. 2010;29:5204–13.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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;150:549–62.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Craig EA. The heat shock response. CRC Crit Rev Biochem. 1985;18:239–80.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Schulz R, Streller F, Scheel AH, Ruschoff J, Reinert MC, Dobbelstein M, et al. HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell Death Dis. 2014;5, e980.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bellmann K, Jaattela M, Wissing D, Burkart V, Kolb H. Heat shock protein hsp70 overexpression confers resistance against nitric oxide. FEBS Lett. 1996;391:185–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Simon MM, Reikerstorfer A, Schwarz A, Krone C, Luger TA, Jaattela M, et al. Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release. J Clin Invest. 1995;95:926–33.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jaattela M. Escaping cell death: survival proteins in cancer. Exp Cell Res. 1999;248:30–43.CrossRefPubMedGoogle Scholar
  24. 24.
    Zylicz M, King FW, Wawrzynow A. Hsp70 interactions with the p53 tumour suppressor protein. EMBO J. 2001;20:4634–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fourie AM, Hupp TR, Lane DP, Sang BC, Barbosa MS, Sambrook JF, et al. HSP70 binding sites in the tumor suppressor protein p53. J Biol Chem. 1997;272:19471–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Kumar S, Tomar MS, Acharya A. HSF1-mediated regulation of tumor cell apoptosis: a novel target for cancer therapeutics. Future Oncol. 2013;9:1573–86.CrossRefPubMedGoogle Scholar
  27. 27.
    Ciocca DR, Calderwood SK. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 2005;10:86–103.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–30.CrossRefPubMedGoogle Scholar
  29. 29.
    Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–70.PubMedGoogle Scholar
  30. 30.
    Chen Z, Lu W, Garcia-Prieto C, Huang P. The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr. 2007;39:267–74.CrossRefPubMedGoogle Scholar
  31. 31.
    DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.CrossRefPubMedGoogle Scholar
  32. 32.
    Gatenby RA, Gillies RJ. Glycolysis in cancer: a potential target for therapy. Int J Biochem Cell Biol. 2007;39:1358–66.CrossRefPubMedGoogle Scholar
  33. 33.
    Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008;49 Suppl 2:24S–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9:425–34.CrossRefPubMedGoogle Scholar
  36. 36.
    Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science. 2006;312:1650–3.CrossRefPubMedGoogle Scholar
  37. 37.
    Schieber MS, Chandel NS. ROS links glucose metabolism to breast cancer stem cell and EMT phenotype. Cancer Cell. 2013;23:265–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12.CrossRefPubMedGoogle Scholar
  39. 39.
    Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A. 1992;89:10578–82.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tan M, Lan KH, Yao J, Lu CH, Sun M, Neal CL, et al. Selective inhibition of ErbB2-overexpressing breast cancer in vivo by a novel TAT-based ErbB2-targeting signal transducers and activators of transcription 3-blocking peptide. Cancer Res. 2006;66:3764–72.CrossRefPubMedGoogle Scholar
  41. 41.
    Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y, et al. ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. Cancer Res. 2005;65:1858–67.CrossRefPubMedGoogle Scholar
  42. 42.
    Zhao YH, Zhou M, Liu H, Ding Y, Khong HT, Yu D, et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene. 2009;28:3689–701.CrossRefPubMedGoogle Scholar
  43. 43.
    Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763–77.CrossRefPubMedGoogle Scholar
  44. 44.
    Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer. 2009;115:5651–61.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.CrossRefPubMedGoogle Scholar
  47. 47.
    Gordan JD, Simon MC. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev. 2007;17:71–7.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.CrossRefPubMedGoogle Scholar
  49. 49.
    Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62:1613–8.PubMedGoogle Scholar
  50. 50.
    Cobaleda C, Perez-Caro M, Vicente-Duenas C, Sanchez-Garcia I. Function of the zinc-finger transcription factor SNAI2 in cancer and development. Annu Rev Genet. 2007;41:41–61.CrossRefPubMedGoogle Scholar
  51. 51.
    Carpenter RL, Paw I, Dewhirst MW, Lo HW. Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells. Oncogene. 2014.Google Scholar
  52. 52.
    Csermely P. A nonconventional role of molecular chaperones: involvement in the cytoarchitecture. News Physiol Sci. 2001;16:123–6.PubMedGoogle Scholar
  53. 53.
    Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501.CrossRefPubMedGoogle Scholar
  54. 54.
    Kroeger PE, Morimoto RI. Selection of new HSF1 and HSF2 DNA-binding sites reveals difference in trimer cooperativity. Mol Cell Biol. 1994;14:7592–603.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ma ZN, Cao Y. [The relationship between the polymerization of HSF1 and the expression of IL-1beta, TNF-alpha mRNA of monocytes in fever rabbits]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2006;22:445–9.Google Scholar
  56. 56.
    Singh IS, He JR, Calderwood S, Hasday JD. A high affinity HSF-1 binding site in the 5′-untranslated region of the murine tumor necrosis factor-alpha gene is a transcriptional repressor. J Biol Chem. 2002;277:4981–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004;6:97–105.CrossRefPubMedGoogle Scholar
  58. 58.
    Jacobs AT, Marnett LJ. HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins. J Biol Chem. 2009;284:9176–83.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005;65:10669–73.CrossRefPubMedGoogle Scholar
  60. 60.
    Chou SD, Murshid A, Eguchi T, Gong J, Calderwood SK. HSF1 regulation of beta-catenin in mammary cancer cells through control of HuR/elavL1 expression. Oncogene. 2014.Google Scholar
  61. 61.
    Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23:6771–90.CrossRefPubMedGoogle Scholar
  62. 62.
    Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA. Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol. 1997;137:481–92.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.CrossRefPubMedGoogle Scholar
  64. 64.
    Viala E, Pouyssegur J. Regulation of tumor cell motility by ERK mitogen-activated protein kinases. Ann N Y Acad Sci. 2004;1030:208–18.CrossRefPubMedGoogle Scholar
  65. 65.
    Ciocca DR, Gago FE, Fanelli MA, Calderwood SK. Co-expression of steroid receptors (estrogen receptor alpha and/or progesterone receptors) and Her-2/neu: clinical implications. J Steroid Biochem Mol Biol. 2006;102:32–40.CrossRefPubMedGoogle Scholar
  66. 66.
    O'Callaghan-Sunol C, Sherman MY. Heat shock transcription factor (HSF1) plays a critical role in cell migration via maintaining MAP kinase signaling. Cell Cycle. 2006;5:1431–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Dai C, Santagata S, Tang Z, Shi J, Cao J, Kwon H, et al. Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. J Clin Invest. 2012;122:3742–54.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Chen YF, Dong Z, Xia Y, Tang J, Peng L, Wang S, et al. Nucleoside analog inhibits microRNA-214 through targeting heat-shock factor 1 in human epithelial ovarian cancer. Cancer Sci. 2013;104:1683–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Das S, Bhattacharyya NP. Heat shock factor 1 regulates hsa-miR-432 expression in human cervical cancer cell line. Biochem Biophys Res Commun. 2014.Google Scholar
  70. 70.
    Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71:3–7.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    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;27:1886–93.CrossRefPubMedGoogle Scholar
  72. 72.
    Yang X, Wang J, Liu S, Yan Q. HSF1 and Sp1 regulate FUT4 gene expression and cell proliferation in breast cancer cells. J Cell Biochem. 2014;115:168–78.CrossRefPubMedGoogle Scholar
  73. 73.
    Kajita K, Kuwano Y, Kitamura N, Satake Y, Nishida K, Kurokawa K, et al. Ets1 and heat shock factor 1 regulate transcription of the transformer 2beta gene in human colon cancer cells. J Gastroenterol. 2013;48:1222–33.CrossRefPubMedGoogle Scholar
  74. 74.
    Sawai M, Ishikawa Y, Ota A, Sakurai H. The proto-oncogene JUN is a target of the heat shock transcription factor HSF1. FEBS J. 2013;280:6672–80.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Sufang Jiang
    • 1
  • Kailing Tu
    • 1
  • Qiang Fu
    • 1
  • David C. Schmitt
    • 2
  • Lan Zhou
    • 3
  • Na Lu
    • 4
  • Yuhua Zhao
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic MedicineSichuan UniversityChengduChina
  2. 2.Mitchell Cancer InstituteUniversity of South AlabamaMobileUSA
  3. 3.Department of Anatomy, West China School of Preclinical and Forensic MedicineSichuan UniversityChengduChina
  4. 4.Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina

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