Tumor Biology

, Volume 36, Issue 12, pp 9661–9665 | Cite as

Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling

  • Shun Li
  • Xiao Liu
  • Xiangrong Chen
  • Liu Zhang
  • Xiangyu Wang
Research Article


Histone deacetylases (HDACs) play a role in the tumorigenesis of glioblastoma multiforme (GBM), whereas the underlying mechanism has not been elucidated. Here, we reported significantly higher HDAC6 levels in GBM from the patients. GBM cell growth was significantly inhibited by ACY-1215, a specific HDAC6 inhibitor. Further analyses show that HDAC6 may promote growth of GBM cells through inhibition of SMAD2 phosphorylation to downregulate p21. Thus, our data demonstrate a previously unrecognized regulation pathway in that HDAC6 increases GBM growth through attenuating transforming growth factor β (TGFβ) receptor signaling.




Conflicts of interest



  1. 1.
    Bi G, Jiang G. The molecular mechanism of HDAC inhibitors in anticancer effects. Cell Mol Immunol. 2006;3:285–90.PubMedGoogle Scholar
  2. 2.
    Secrist JP, Zhou X, Richon VM. HDAC inhibitors for the treatment of cancer. Curr Opin Investig Drugs. 2003;4:1422–7.PubMedGoogle Scholar
  3. 3.
    de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACS): characterization of the classical HDAC family. Biochem J. 2003;370:737–49.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Chen J, Huang Q, Wang F. Inhibition of FoxO1 nuclear exclusion prevents metastasis of glioblastoma. Tumour Biol. 2014;35:7195–200.CrossRefPubMedGoogle Scholar
  5. 5.
    Li S, Gao Y, Ma W, Guo W, Zhou G, et al. EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biol. 2014;35:5593–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Wang F, Xiao W, Sun J, Han D, Zhu Y: MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol 2014Google Scholar
  7. 7.
    Bezecny P. Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience. Med Oncol. 2014;31:985.CrossRefPubMedGoogle Scholar
  8. 8.
    Adamopoulou E, Naumann U. HDAC inhibitors and their potential applications to glioblastoma therapy. Oncoimmunol. 2013;2:e25219.CrossRefGoogle Scholar
  9. 9.
    Jin H, Liang L, Liu L, Deng W, Liu J. HDAC inhibitor DWP0016 activates p53 transcription and acetylation to inhibit cell growth in U251 glioblastoma cells. J Cell Biochem. 2013;114:1498–509.CrossRefPubMedGoogle Scholar
  10. 10.
    Asklund T, Kvarnbrink S, Holmlund C, Wibom C, Bergenheim T, Henriksson R, et al. Synergistic killing of glioblastoma stem-like cells by bortezomib and HDAC inhibitors. Anticancer Res. 2012;32:2407–13.PubMedGoogle Scholar
  11. 11.
    Bajbouj K, Mawrin C, Hartig R, Schulze-Luehrmann J, Wilisch-Neumann A, Roessner A, et al. P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells. J Neurooncol. 2012;107:503–16.CrossRefPubMedGoogle Scholar
  12. 12.
    Sawa H, Murakami H, Ohshima Y, Murakami M, Yamazaki I, Tamura Y, et al. Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells. Brain Tumour Pathol. 2002;19:77–81.CrossRefGoogle Scholar
  13. 13.
    Svechnikova I, Almqvist PM, Ekstrom TJ. HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. Int J Oncol. 2008;32:821–7.PubMedGoogle Scholar
  14. 14.
    Massague J. TGFbeta in cancer. Cell. 2008;134:215–30.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111:E1211–20.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yi JJ, Barnes AP, Hand R, Polleux F, Ehlers MD. TGF-beta signaling specifies axons during brain development. Cell. 2010;142:144–57.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ewen ME, Sluss HK, Whitehouse LL, Livingston DM. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell. 1993;74:1009–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, et al. TGFbeta receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diab. 2013;62:1217–26.CrossRefGoogle Scholar
  20. 20.
    Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, et al. USP15 stabilizes TGF-beta receptor i and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma. Nat Med. 2012;18:429–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang M, Kleber S, Rohrich M, Timke C, Han N, Tuettenberg J. Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 2011;71:7155–67.CrossRefPubMedGoogle Scholar
  22. 22.
    Grzmil M, Morin Jr P, Lino MM, Merlo A, Frank S, Wang Y, et al. MAP kinase-interacting kinase 1 regulates SMAD2-dependent TGF-beta signaling pathway in human glioblastoma. Cancer Res. 2011;71:2392–402.CrossRefPubMedGoogle Scholar
  23. 23.
    Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G, Carmona MA, et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell. 2010;18:655–68.CrossRefPubMedGoogle Scholar
  24. 24.
    Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, Cuartas I, et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell. 2009;15:315–27.CrossRefPubMedGoogle Scholar
  25. 25.
    Emori T, Kitamura K, Okazaki K. Nuclear Smad7 overexpressed in mesenchymal cells acts as a transcriptional corepressor by interacting with HDAC-1 and E2F to regulate cell cycle. Biol Open. 2012;1:247–60.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ehnert S, Zhao J, Pscherer S, Freude T, Dooley S, Kolk A, et al. Transforming growth factor beta1 inhibits bone morphogenic protein (BMP)-2 and BMP-7 signaling via upregulation of Ski-related novel protein N (SnoN): possible mechanism for the failure of bmp therapy. BMC Med. 2012;10:101.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cho JS, Moon YM, Park IH, Um JY, Moon JH, Park SJ, et al. Epigenetic regulation of myofibroblast differentiation and extracellular matrix production in nasal polyp-derived fibroblasts. Clin Exp Allergy. 2012;42:872–82.CrossRefPubMedGoogle Scholar
  28. 28.
    Barter MJ, Pybus L, Litherland GJ, Rowan AD, Clark IM, Edwards DR, et al. HDAC-mediated control of ERK- and PI3K-dependent TGF-beta-induced extracellular matrix-regulating genes. Matrix Biol. 2010;29:602–12.CrossRefPubMedGoogle Scholar
  29. 29.
    Glenisson W, Castronovo V, Waltregny D. Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochim Biophys Acta. 2007;1773:1572–82.CrossRefPubMedGoogle Scholar
  30. 30.
    Qiu P, Ritchie RP, Gong XQ, Hamamori Y, Li L. Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbeta1 signaling. Biochem Biophys Res Commun. 2006;348:351–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Bai S, Cao X. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-beta signaling. J Biol Chem. 2002;277:4176–82.CrossRefPubMedGoogle Scholar
  32. 32.
    Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012;119:2579–89.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Huang S, Liao Q, Li L, Xin D. PTTG1 inhibits SMAD3 in prostate cancer cells to promote their proliferation. Tumour Biol. 2014;35:6265–70.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang G, Zhao Q, Yu S, Lin R, Yi X: Pttg1 inhibits TGFbeta signaling in breast cancer cells to promote their growth. Tumour Biol 2014 in pressGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shun Li
    • 1
    • 2
  • Xiao Liu
    • 1
  • Xiangrong Chen
    • 3
  • Liu Zhang
    • 4
  • Xiangyu Wang
    • 1
    • 4
  1. 1.Department of Neurosurgery, Zhujiang Hospital, The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and RegenerationSouthern Medical UniversityGuangzhouChina
  2. 2.Department of NeurosurgeryAffiliated Hospital of North Sichuan Medical CollegeNanchongChina
  3. 3.Department of NeurosurgeryThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
  4. 4.Department of NeurosurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouChina

Personalised recommendations