Dataset Information

SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of "cancer cells with neural stemness" in a p53-dependent manner.

ABSTRACT:

Background

Cancer stemness, observed in several types of glioma stem cells (GSCs), has been demonstrated to be an important barrier for efficient cancer therapy. We have previously reported that cancerous neural stem cells (F3.Ras.CNSCs), derived from immortalized human neural stem cells by a single oncogenic stimulation, form glial tumors in vivo.

Method

We searched for a commonly expressed stress modulator in both F3.Ras.CNSCs and GSCs and identified silent mating type information regulation 2, homolog (SIRT1) as a key factor in maintaining cancer stemness.

Result

We demonstrate that the expression of SIRT1, expressed in "cancer cells with neural stemness," is critical not only for the maintenance of stem cells, but also for oncogenic transformation. Interestingly, SIRT1 is essential for the survival and tumorigenicity of F3.Ras.CNSCs and GSCs but not for the U87 glioma cell line.

Conclusion

These results indicate that expression of SIRT1 in cancer cells with neural stemness plays an important role in suppressing p53-dependent tumor surveillance, the abrogation of which may be responsible not only for inducing oncogenic transformation but also for retaining the neural cancer stemness of the cells, suggesting that SIRT1 may be a putative therapeutic target in GSCs.

SUBMITTER: Lee JS

PROVIDER: S-EPMC4483050 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Publications

SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of "cancer cells with neural stemness" in a p53-dependent manner.

Lee Ji-Seon JS Park Jeong-Rak JR Kwon Ok-Seon OS Lee Tae-Hee TH Nakano Ichiro I Miyoshi Hiroyuki H Chun Kwang-Hoon KH Park Myung-Jin MJ Lee Hong Jun HJ Kim Seung U SU Cha Hyuk-Jin HJ

Neuro-oncology 20140805 1

<h4>Background</h4>Cancer stemness, observed in several types of glioma stem cells (GSCs), has been demonstrated to be an important barrier for efficient cancer therapy. We have previously reported that cancerous neural stem cells (F3.Ras.CNSCs), derived from immortalized human neural stem cells by a single oncogenic stimulation, form glial tumors in vivo.<h4>Method</h4>We searched for a commonly expressed stress modulator in both F3.Ras.CNSCs and GSCs and identified silent mating type informati ...[more]

PMID: 25096191

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Project description:BACKGROUND:The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious. METHODS:We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided. RESULTS:We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1? destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers. CONCLUSIONS:Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth.

Dataset Information

SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of "cancer cells with neural stemness" in a p53-dependent manner.

Background

Method

Result

Conclusion

Publications

SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of "cancer cells with neural stemness" in a p53-dependent manner.

Similar Datasets

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