Abstract
Glioblastoma multiforme (GBM) is characterized by poor therapeutic response and poor overall survival. It is crucial that more effective therapies be developed for the treatment of GBM. Inhibitor of DNA binding protein-1 (ID1) has been shown to maintain the self-renewal capacity of neural stem cells and might be involved in the therapeutic resistance of GBM. In the present study, we explored survival data from the The Cancer Genome Atalas database that were based on ID1 expression for patients diagnosed with primary GBMs. Interestingly, patients with high ID1 expression had better survival than patients with low ID1 expression, and a strong correlation was found between radiotherapy efficacy, ID1 expression, and overall survival. We further investigated the relationship between ID1 expression and the radiosensitivity of glioblastoma using glioblastoma cell lines. The clonogenic formation assay showed that U87 ID1-shRNA cells were much less sensitive to radiation. Moreover, both the results of the γH2AX foci staining assay and the comet assay further revealed that ID1 negatively regulates DNA repair processes by downregulating the expression of genes such as DNA ligase IV (LIG4) and ataxia-telangiectasia-mutated. Additionally, ID1 induces G2/M arrest in U87 cells. Taken together, these results suggest that ID1 may be a new prognostic marker for GBM and have important implications for the therapeutic strategies used to treat GBM patients.
Similar content being viewed by others
References
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.
Patel M, Vogelbaum MA, Barnett GH, Jalali R, Ahluwalia MS. Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions. Expert Opin Investig Drugs. 2012;21(9):1247–66.
Ohka F, Natsume A, Wakabayashi T. Current trends in targeted therapies for glioblastoma multiforme. Neurol Res Int. 2012;2012:1–13.
Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008;8(3):180–92.
Zhu Y, Hu J, Hu Y, Liu W. Targeting DNA repair pathways: a novel approach to reduce cancer therapeutic resistance. Cancer Treat Rev. 2009;35(7):590–6.
Kyle S, Thomas HD, Mitchell J, Curtin NJ. Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer. Br J Radiol. 2008;81(1):S6–11.
Evers B, Schut E, van der Burg E, Braumuller TM, Egan DA, Holstege H, et al. A high-throughput pharmaceutical screen identifies compounds with specific toxicity against BRCA2-deficient tumors. Clin Cancer Res. 2010;16(1):99–108.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.
Sikder HA, Devlin MK, Dunlap S, Ryu B, Alani RM. Id proteins in cell growth and tumorigenesis. Cancer Cell. 2003;3(6):525–30.
Zhang X, Ling MT, Wang Q, Lau CK, Leung SC, Lee TK, et al. Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells. J Biol Chem. 2007;282(46):33284–94.
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(6):655–68.
Ding R, Han S, Lu Y, Guo C, Xie H, Zhang N, et al. Overexpressed Id-1 is associated with patient prognosis and HBx expression in hepatitis B virus-related hepatocellular carcinoma. Cancer Biol Ther. 2010;10(3):299–307.
Dong Z, Liu S, Zhou C, Sumida T, Hamakawa H, Chen Z, et al. Overexpression of Id-1 is associated with tumor angiogenesis and poor clinical outcome in oral squamous cell carcinoma. Oral Oncol. 2010;46(3):154–7.
Geng H, Rademacher BL, Pittsenbarger J, Huang CY, Harvey CT, Lafortune MC, et al. ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21. Cancer Res. 2010;70(8):3239–48.
Meng Q, Jia Z, Wang W, Li B, Ma K, Zhou C. Inhibitor of DNA binding 1 (Id1) induces differentiation and proliferation of mouse embryonic carcinoma P19CL6 cells. Biochem Biophys Res Commun. 2011;412(2):253–9.
Yageta M, Tsunoda H, Yamanaka T, Nakajima T, Tomooka Y, Tsuchida N, et al. The adenovirus E1A domains required for induction of DNA rereplication in G2/M arrested cells coincide with those required for apoptosis. Oncogene. 1999;18(34):4767–76.
Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59(4):928–42.
O’Brien CA, Kreso A, Ryan P, Hermans KG, Gibson L, Wang Y, et al. ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell. 2012;21(6):777–92.
Ciarrocchi A, Jankovic V, Shaked Y, Nolan DJ, Mittal V, Kerbel RS, et al. Id1 restrains p21 expression to control endothelial progenitor cell formation. PLoS ONE. 2007;2(12):e1338.
Prabhu S, Ignatova A, Park ST, Sun XH. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol. 1997;17(10):5888–96.
Mauro M, Rego MA, Boisvert RA, Esashi F, Cavallo F, Jasin M, et al. p21 promotes error-free replication-coupled DNA double-strand break repair. Nucleic Acids Res. 2012;40(17):8348-60.
Dolezalova D, Mraz M, Barta T, Plevova K, Vinarsky V, Holubcova Z, et al. MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. Stem cells. 2012;30(7):1362–72.
Koike M, Yutoku Y, Koike A. Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation. Biochem Biophys Res Commun. 2011;412(1):39–43.
Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev. 2005;5(8):603–14.
Shen Y, Wang Y, Sheng K, Fei X, Guo Q, Larner J, et al. Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma. Cell Death Disease. 2011;2:e241.
Pillai S, Rizwani W, Li X, Rawal B, Nair S, Schell MJ, et al. ID1 facilitates the growth and metastasis of non-small cell lung cancer in response to nicotinic acetylcholine receptor and epidermal growth factor receptor signaling. Mol Cell Biol. 2011;31(14):3052–67.
Jankovic V, Ciarrocchi A, Boccuni P, DeBlasio T, Benezra R, Nimer SD. Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells. Proc Natl Acad Sci USA. 2007;104(4):1260–5.
Barrett LE, Granot Z, Coker C, Iavarone A, Hambardzumyan D, Holland EC, et al. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell. 2012;21(1):11–24.
Li LJ, Zhong LF, Jiang LP, Geng CY, Zou LJ. beta-Elemene radiosensitizes lung cancer A549 cells by enhancing DNA damage and inhibiting DNA repair. Phytother Res. 2011;25(7):1095–7.
Masuda Y, Kamiya K. Molecular nature of radiation injury and DNA repair disorders associated with radiosensitivity. Int J Hematol. 2012;95(3):239–45.
Acknowledgments
This work was supported by a project aimed at building key clinical disciplines at the hospital (NO.RJ.4101307) and by grants from the Shanghai government (NO.0952nm03900) and Shanghai Jiao Tong University School of Medicine (NO.BXJ201024).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guo, Q., Guo, P., Mao, Q. et al. ID1 affects the efficacy of radiotherapy in glioblastoma through inhibition of DNA repair pathways. Med Oncol 30, 325 (2013). https://doi.org/10.1007/s12032-012-0325-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-012-0325-6