文章：

CELF2通过表观遗传抑制SOX3维持增殖性/OLIG2+胶质母细胞瘤细胞表型

CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3

原文发布日期：18 October 2023

DOI: 10.3390/cancers15205038

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

胶质母细胞瘤（GBs）是一种无法治愈的脑肿瘤。细胞毒性治疗后侵袭性干细胞样肿瘤细胞的持续存在会损害治疗效果，导致GBM复发。迫使GBM细胞不可逆地放弃其侵袭性干细胞样表型，可能为传统细胞毒性治疗提供一种替代方案。本文研究表明，RNA结合蛋白CELF2在有丝分裂和OLIG2阳性的GBM细胞中高表达，而在分化和非有丝分裂细胞中则被miR-199a-3p下调，这体现了GBM肿瘤内异质性。利用患者来源细胞和人GBM样本，我们证明CELF2在维持具有克隆和致瘤特性的增殖/OLIG2细胞表型中起关键作用。事实上，我们发现患者来源的GSCs中CELF2缺失会显著降低裸鼠脑内肿瘤生长。我们进一步证明CELF2促进TRIM28和G9a表达，从而驱动H3K9me3表观遗传特征，导致SOX3基因沉默。因此，在人GBM样本中与OLIG2和Ki67表达呈正相关的CELF2，与SOX3和miR-199a-3p呈负相关。相应地，在CELF2缺失的患者来源细胞中敲除SOX3可恢复增殖能力和OLIG2表达。最后，SOX3表达水平高于中位值的患者往往具有更长的预期寿命。因此，CELF2是GBM恶性潜能的关键靶点，在开发新型抗癌策略时值得关注。

原文链接：

CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3