| Title |
The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells
|
|---|---|
| Published in |
Acta Neuropathologica, August 2014
|
| DOI | 10.1007/s00401-014-1334-7 |
| Pubmed ID | |
| Authors |
Yinxing Liu, Misty R. Gilbert, Natasha Kyprianou, Vivek M. Rangnekar, Craig Horbinski |
| 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. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Science communicators (journalists, bloggers, editors) | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Brazil | 1 | 4% |
| Unknown | 25 | 96% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 7 | 27% |
| Student > Bachelor | 4 | 15% |
| Researcher | 4 | 15% |
| Student > Master | 3 | 12% |
| Professor > Associate Professor | 2 | 8% |
| Other | 3 | 12% |
| Unknown | 3 | 12% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 7 | 27% |
| Agricultural and Biological Sciences | 6 | 23% |
| Neuroscience | 3 | 12% |
| Biochemistry, Genetics and Molecular Biology | 3 | 12% |
| Unknown | 7 | 27% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 25 August 2014.
All research outputs
#20,235,415
of 22,761,738 outputs
Outputs from Acta Neuropathologica
#2,275
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Outputs of similar age
#197,545
of 235,512 outputs
Outputs of similar age from Acta Neuropathologica
#23
of 24 outputs
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