2026-06-14T03:31:58Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/78932025-06-13T09:26:12Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617
Repisalud
author
Kuciak, Monika
author
Mas, Christophe
author
Borges, Isabel
author
Sánchez-Gómez, Pilar
author
Ruiz i Altaba, Ariel
funder
Fondation Eclosion
funder
James McDonnell Brain Cancer Award
funder
Republique et Canton de Geneve. Département de l instruction publique, de la formation et de la jeunesse (DIP) (Suiza)
2019-07-11T10:03:10Z
2019-07-11T10:03:10Z
2019
Sci Rep. 2019 Mar 7;9(1):3891
10.1038/s41598-019-39473-y
2045-2322
2045-2322
Scientific Reports
30846719
http://hdl.handle.net/20.500.12105/7893
Targeting stemness promises new therapeutic strategies against highly invasive tumors. While a number of approaches are being tested, inhibiting the core transcription regulatory network of cancer stem cells is an attractive yet challenging possibility. Here we have aimed to provide the proof of principle for a strategy, previously used in developmental studies, to directly repress the targets of a salient stemness and pluripotency factor: NANOG. In doing so we expected to inhibit the expression of so far unknown mediators of pro-tumorigenic NANOG function. We chose NANOG since previous work showed the essential requirement for NANOG activity for human glioblastoma (GBM) growth in orthotopic xenografts, and it is apparently absent from many adult human tissues thus likely minimizing unwanted effects on normal cells. NANOG repressor chimeras, which we name NANEPs, bear the DNA-binding specificity of NANOG through its homeodomain (HD), and this is linked to transposable human repressor domains. We show that in vitro and in vivo, NANEP5, our most active NANEP with a HES1 repressor domain, mimics knock-down (kd) of NANOG function in GBM cells. Competition orthotopic xenografts also reveal the effectiveness of NANEP5 in a brain tumor context, as well as the specificity of NANEP activity through the abrogation of its function via the introduction of specific mutations in the HD. The transcriptomes of cells expressing NANEP5 reveal multiple potential mediators of pro-tumorigenic NANEP/NANOG action including intercellular signaling components. The present results encourage further studies on the regulation of context-dependent NANEP abundance and function, and the development of NANEP-based anti-cancer therapies.
eng
Chimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manner
research article
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Chimeric_NANOG_Repressors_Inhibit_2019.pdf
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Chimeric_NANOG_Repressors_Inhibit_2019.pdf.txt