SUMOylation in Glioblastoma: A Novel Therapeutic Target

doi:10.3390/ijms20081853

Review

. 2019 Apr 15;20(8):1853.

doi: 10.3390/ijms20081853.

SUMOylation in Glioblastoma: A Novel Therapeutic Target

Brandon M Fox^{1

2}, Andrew Janssen³, Dagoberto Estevez-Ordonez⁴, Florian Gessler⁵, Nunzio Vicario⁶, Gustavo Chagoya⁷, Galal Elsayed⁸, Houman Sotoudeh⁹, William Stetler¹⁰, Gregory K Friedman^{11

12

13}, Joshua D Bernstock^{14

15}

Affiliations

¹ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. bmfox@uab.edu.
² Medical Scientist Training Program, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 121, Birmingham, AL 35294, USA. bmfox@uab.edu.
³ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. janssen@uab.edu.
⁴ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. dagoestevez@gmail.com.
⁵ Department of Neurosurgery, University Hospital Frankfurt, Goethe-University, Schleusenweg 2-16, 60528 Frankfurt, Germany. flo.gessler@gmail.com.
⁶ Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Via S. Sofia n. 97, Torre Biologica, 95123 Catania, Italy. vicarionunzio@gmail.com.
⁷ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. gchagoya@uabmc.edu.
⁸ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. gelsayed@uabmc.edu.
⁹ Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Jefferson Tower N419-619 19th Street South, Birmingham, AL 35223, USA. HSotoudeh@uabmc.edu.
¹⁰ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. wstetler@uabmc.edu.
¹¹ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. GFriedman@peds.uab.edu.
¹² Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Jefferson Tower N419-619 19th Street South, Birmingham, AL 35223, USA. GFriedman@peds.uab.edu.
¹³ Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Lowder 512, 1600 7th Avenue South, Birmingham, AL 35223, USA. GFriedman@peds.uab.edu.
¹⁴ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. jdb82@uab.edu.
¹⁵ Medical Scientist Training Program, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 121, Birmingham, AL 35294, USA. jdb82@uab.edu.

PMID: 30991648
PMCID: PMC6514907
DOI: 10.3390/ijms20081853

Review

SUMOylation in Glioblastoma: A Novel Therapeutic Target

Brandon M Fox et al. Int J Mol Sci. 2019.

. 2019 Apr 15;20(8):1853.

doi: 10.3390/ijms20081853.

Authors

Affiliations

¹ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. bmfox@uab.edu.
² Medical Scientist Training Program, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 121, Birmingham, AL 35294, USA. bmfox@uab.edu.
³ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. janssen@uab.edu.
⁴ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. dagoestevez@gmail.com.
⁵ Department of Neurosurgery, University Hospital Frankfurt, Goethe-University, Schleusenweg 2-16, 60528 Frankfurt, Germany. flo.gessler@gmail.com.
⁶ Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Via S. Sofia n. 97, Torre Biologica, 95123 Catania, Italy. vicarionunzio@gmail.com.
⁷ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. gchagoya@uabmc.edu.
⁸ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. gelsayed@uabmc.edu.
⁹ Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Jefferson Tower N419-619 19th Street South, Birmingham, AL 35223, USA. HSotoudeh@uabmc.edu.
¹⁰ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. wstetler@uabmc.edu.
¹¹ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. GFriedman@peds.uab.edu.
¹² Division of Neuroradiology, Department of Radiology, University of Alabama at Birmingham, Jefferson Tower N419-619 19th Street South, Birmingham, AL 35223, USA. GFriedman@peds.uab.edu.
¹³ Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Lowder 512, 1600 7th Avenue South, Birmingham, AL 35223, USA. GFriedman@peds.uab.edu.
¹⁴ Department of Neurosurgery, University of Alabama at Birmingham, 1060 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35223, USA. jdb82@uab.edu.
¹⁵ Medical Scientist Training Program, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 121, Birmingham, AL 35294, USA. jdb82@uab.edu.

PMID: 30991648
PMCID: PMC6514907
DOI: 10.3390/ijms20081853

Abstract

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.

Keywords: SUMO1-3; SUMOylation; glioblastoma (GBM); post-translational modifications (PTMs).

PubMed Disclaimer

Conflict of interest statement

J.D.B has positions/equity in CITC Ltd and Avidea Technologies.

Figures

**Figure 1**
Enhancement of SUMOylation in glioblastoma contributes to alterations in multiple cellular processes leading to an increased malignant phenotype. Glioblastoma displays an increase in E1 (SAE1), E2 (Ubc9), and E3 (PIAS1 and PIAS3) enzymes leading to global enhancement of SUMOylation and a resultant increase in the SUMOylation level of target proteins. Further, increased expression of SUMO-specific protease (SENP1) has been reported in glioblastoma. Presently, studies have implicated CDK6 and HIF-1α as important loci downstream of these effects that together contribute to cell cycle dysregulation, epithelial-mesenchymal transition, and heightened glycolytic metabolism. DNA double-strand break repair has additionally been associated with perturbations in SUMOylation. Together, these altered cellular processes give rise to an enhanced malignant phenotype in glioblastoma including uncontrolled growth, increased invasion and aggressiveness, a malignant bioenergetics profile with Warburg effect, and resistance to ionizing radiation. Targeting SUMOylation may represent a therapeutic approach to reverse the pathologic consequences of enhanced SUMOylation in glioblastoma. Available therapeutic agents known to inhibit SUMOylation are identified along with their targets in the SUMOylation pathway.

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References

1. Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., Ludwin S.K., Allgeier A., Fisher B., Belanger K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7. - DOI - PubMed
1. Polivka J., Jr., Polivka J., Holubec L., Kubikova T., Priban V., Hes O., Pivovarcikova K., Treskova I. Advances in Experimental targeted therapy and immunotherapy for patients with glioblastoma multiforme. Anticancer Res. 2017;37:21–33. doi: 10.21873/anticanres.11285. - DOI - PubMed
1. Touat M., Idbaih A., Sanson M., Ligon K.L. Glioblastoma targeted therapy: Updated approaches from recent biological insights. Ann. Oncol. 2017;28:1457–1472. doi: 10.1093/annonc/mdx106. - DOI - PMC - PubMed
1. Mahajan R., Delphin C., Guan T., Gerace L., Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997;88:97–107. doi: 10.1016/S0092-8674(00)81862-0. - DOI - PubMed
1. Flotho A., Melchior F. Sumoylation: A regulatory protein modification in health and disease. Annu. Rev. Biochem. 2013;82:357–385. doi: 10.1146/annurev-biochem-061909-093311. - DOI - PubMed

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[1] Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., Ludwin S.K., Allgeier A., Fisher B., Belanger K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7. - DOI - PubMed

[2] Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., Ludwin S.K., Allgeier A., Fisher B., Belanger K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7. - DOI - PubMed

[3] Polivka J., Jr., Polivka J., Holubec L., Kubikova T., Priban V., Hes O., Pivovarcikova K., Treskova I. Advances in Experimental targeted therapy and immunotherapy for patients with glioblastoma multiforme. Anticancer Res. 2017;37:21–33. doi: 10.21873/anticanres.11285. - DOI - PubMed

[4] Polivka J., Jr., Polivka J., Holubec L., Kubikova T., Priban V., Hes O., Pivovarcikova K., Treskova I. Advances in Experimental targeted therapy and immunotherapy for patients with glioblastoma multiforme. Anticancer Res. 2017;37:21–33. doi: 10.21873/anticanres.11285. - DOI - PubMed

[5] Touat M., Idbaih A., Sanson M., Ligon K.L. Glioblastoma targeted therapy: Updated approaches from recent biological insights. Ann. Oncol. 2017;28:1457–1472. doi: 10.1093/annonc/mdx106. - DOI - PMC - PubMed

[6] Touat M., Idbaih A., Sanson M., Ligon K.L. Glioblastoma targeted therapy: Updated approaches from recent biological insights. Ann. Oncol. 2017;28:1457–1472. doi: 10.1093/annonc/mdx106. - DOI - PMC - PubMed

[7] Mahajan R., Delphin C., Guan T., Gerace L., Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997;88:97–107. doi: 10.1016/S0092-8674(00)81862-0. - DOI - PubMed

[8] Mahajan R., Delphin C., Guan T., Gerace L., Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997;88:97–107. doi: 10.1016/S0092-8674(00)81862-0. - DOI - PubMed

[9] Flotho A., Melchior F. Sumoylation: A regulatory protein modification in health and disease. Annu. Rev. Biochem. 2013;82:357–385. doi: 10.1146/annurev-biochem-061909-093311. - DOI - PubMed

[10] Flotho A., Melchior F. Sumoylation: A regulatory protein modification in health and disease. Annu. Rev. Biochem. 2013;82:357–385. doi: 10.1146/annurev-biochem-061909-093311. - DOI - PubMed

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SUMOylation in Glioblastoma: A Novel Therapeutic Target

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SUMOylation in Glioblastoma: A Novel Therapeutic Target

Authors

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Abstract

Conflict of interest statement

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