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The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells

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Abstract

Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild type, those that express more Par-4 have significantly longer median survival (18.4 vs. 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect.

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Acknowledgments

CH was supported by K08 CA155764 (National Cancer Institute), 2P20 RR020171 COBRE pilot grant (National Institute of General Medical Sciences), The Peter and Carmen Lucia Buck Training Program in Translational Clinical Oncology, and the University of Kentucky College of Medicine Physician Scientist Program. This work was also supported by NIH R01 CA060872 (to VMR). This research was supported by the Biospecimen and Tissue Procurement Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). Special thanks to Dana Napier for her excellent histologic expertise, and to Ravshan Burikhanov for his technical assistance. We thank Dr. Hai Yan of Duke University Medical Center for supplying us with the pEGFP-N1-IDH1R132H plasmid, and Drs. Jeremy Rich and Monica Venere of the Cleveland Clinic for patient-derived GBM stem cells. We also thank Dr. Chunming Liu of the University of Kentucky for the renilla luciferase plasmid.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Kentucky, 307 Combs Building, Lexington, KY, 40536, USA

    Yinxing Liu, Misty R. Gilbert, Natasha Kyprianou & Craig Horbinski

  2. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA

    Natasha Kyprianou & Craig Horbinski

  3. Department of Radiation Medicine, University of Kentucky, Lexington, KY, USA

    Vivek M. Rangnekar

  4. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA

    Vivek M. Rangnekar

  5. Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    Natasha Kyprianou, Vivek M. Rangnekar & Craig Horbinski

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  1. Yinxing Liu
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Correspondence to Craig Horbinski.

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Liu, Y., Gilbert, M.R., Kyprianou, N. et al. The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells. Acta Neuropathol 128, 723–732 (2014). https://doi.org/10.1007/s00401-014-1334-7

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