PDF(Pubmed)
Abstract：
The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.
摘要：
驱动神经胶质瘤进展的因素仍然知之甚少。这里,表观遗传调节因子TRIM24被确定为神经胶质瘤进展的驱动因素，其中TRIM24过表达促进HRasV12间变性星形细胞瘤（AA）进展为上皮样GBM（Ep-GBM）样肿瘤。TRIM24与HRasV12的共转染还诱导具有肿瘤蛋白p53基因(TP53)敲低的人神经干细胞(hNSC)的Ep-GBM样转化。此外，TRIM24在临床Ep-GBM标本中高表达。使用单细胞RNA测序（scRNA-Seq），作者表明TRIM24过表达影响肿瘤内异质性和肿瘤微环境.机械上,HRasV12激活RNA输出（PHAX）的磷酸化衔接子，并上调U3小核仁RNA（U3snoRNA）以招募Ku依赖性DNA依赖性蛋白激酶催化亚基（DNA-PKcs）。过表达的TRIM24也被PHAX招募到U3snoRNA，从而促进TRIM24在S767/768残基处的DNA-PKcs磷酸化。磷酸化TRIM24诱导表观基因组和转录因子网络重编程并促进Ep-GBM样转化。用小分子抑制剂NU7441靶向DNA-PKcs与替莫唑胺协同作用以降低Ep-GBM致瘤性并延长动物存活。这些发现为Ep-GBM样转化的表观遗传调控提供了新的见解，并为Ep-GBM患者提出了潜在的治疗策略。
