CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3
by
, , , , , , ,
Laurent Turchi
1,2
,
Nathalie Sakakini
1,
Gaelle Saviane
1,
Béatrice Polo
1,
Mirca Saras Saurty-Seerunghen
3,
Mathieu Gabut
4,5,
Corine Auge Gouillou
6,
Vincent Guerlais
7,
Claude Pasquier
7,
Marie Luce Vignais
8,
Fabien Almairac
1,9,
Hervé Chneiweiss
3,
Marie-Pierre Junier
3,
Fanny Burel-Vandenbos
1,10 and
Thierry Virolle
1,* 1
CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France
2
DRCI, CHU de Nice, 06107 Nice, France
3
CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France
4
Stemness in Gliomas Laboratory, Cancer Initiation and Tumoral Cell Identity (CITI) Department, INSERM 1052, CNRS 5286, Centre Léon Bérard, 69008 Lyon, France
5
Cancer Research Center of Lyon 1, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France
6
UMR 1253, iBrain, Inserm, Université de Tours, 37000 Tours, France
7
CNRS, I3S, Université Côte d’Azur, 06560 Valbonne, France
8
CNRS, INSERM, Institut de Génomique Fonctionnelle, IGF, Université de Montpellier, 34090 Montpellier, France
9
Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, 06107 Nice, France
10
Service d’Anatomopathologie, Hôpital Pasteur, CHU de Nice, 06107 Nice, France
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(20), 5038; https://doi.org/10.3390/cancers15205038
Submission received: 16 June 2023
/
Revised: 23 July 2023
/
Accepted: 10 August 2023
/
Published: 18 October 2023
(This article belongs to the Special Issue Brain Cancer Stem Cells in Children and Adults)
Simple Summary
Glioblastomas, primitive infiltrating brain tumors, are a real public health problem because of their dismal prognosis. The persistence of aggressive tumor stem cells after conventional cytotoxic treatment is one of the major causes of therapeutic failure. The identification of targets involved in the molecular mechanisms repressing the aggressive stem cell phenotype is a relevant approach that offers an alternative to more conventional cytotoxic therapies, which have failed to prevent GBM recurrence. In this study, we have identified the protein CELF2 as being an efficient epigenetic regulator of genes in glioma stem cells (GSCs). CELF2 shapes a H3K9me3-repressive landscape in the SOX3 gene, thereby promoting a proliferating tumor cell phenotype. We found that CELF2 is a major point of tumor vulnerability as its repression is sufficient to convert aggressive tumor cells into cells without the ability to form tumors in vivo. CELF2 is a crucial target that warrants attention for the development of novel anticancer strategies.
Abstract
Glioblastomas (GBs) are incurable brain tumors. The persistence of aggressive stem-like tumor cells after cytotoxic treatments compromises therapeutic efficacy, leading to GBM recurrence. Forcing the GBM cells to irreversibly abandon their aggressive stem-like phenotype may offer an alternative to conventional cytotoxic treatments. Here, we show that the RNA binding protein CELF2 is strongly expressed in mitotic and OLIG2-positive GBM cells, while it is downregulated in differentiated and non-mitotic cells by miR-199a-3p, exemplifying GBM intra-tumor heterogeneity. Using patient-derived cells and human GBM samples, we demonstrate that CELF2 plays a key role in maintaining the proliferative/OLIG2 cell phenotype with clonal and tumorigenic properties. Indeed, we show that CELF2 deficiency in patient-derived GSCs drastically reduced tumor growth in the brains of nude mice. We further show that CELF2 promotes TRIM28 and G9a expression, which drive a H3K9me3 epigenetic profile responsible for the silencing of the SOX3 gene. Thus, CELF2, which is positively correlated with OLIG2 and Ki67 expression in human GBM samples, is inversely correlated with SOX3 and miR-199a-3p. Accordingly, the invalidation of SOX3 in CELF2-deficient patient-derived cells rescued proliferation and OLIG2 expression. Finally, patients expressing SOX3 above the median level of expression tend to have a longer life expectancy. CELF2 is therefore a crucial target for the malignant potential of GBM and warrants attention when developing novel anticancer strategies.
Keywords:
glioblastoma; cancer stem cells; epigenetic; RNA binding protein; H3K9me3; OLIG2; CELF2
