Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Adv. 2022 Oct 7;8(40):eabn2571. doi: 10.1126/sciadv.abn2571. Epub 2022 Oct 5.
Histone 2A (H2A) monoubiquitination is a fundamental epigenetics mechanism of gene expression, which plays a critical role in regulating cell fate. However, it is unknown if H2A ubiquitination is involved in EGFR-driven tumorigenesis. In the current study, we have characterized a previously unidentified oncogenic lncRNA (lncEPAT) that mediates the integration of the dysregulated EGFR pathway with H2A deubiquitination in tumorigenesis. LncEPAT was induced by the EGFR pathway, and high-level lncEPAT expression positively correlated with the glioma grade and predicted poor survival of glioma patients. Mass spectrometry analyses revealed that lncEPAT specifically interacted with deubiquitinase USP16. LncEPAT inhibited USP16's recruitment to chromatin, thereby blocking USP16-mediated H2A deubiquitination and repressing target gene expression, including and . Depletion of lncEPAT promoted USP16-induced cell cycle arrest and cellular senescence, and then repressed GBM cell tumorigenesis. Thus, the EGFR-lncEPAT-ubH2A coupling represents a previously unidentified mechanism for epigenetic gene regulation and senescence resistance during GBM tumorigenesis.
组蛋白 2A（H2A）单泛素化是基因表达的一种基本表观遗传机制，在调节细胞命运方面起着关键作用。然而，目前尚不清楚 H2A 泛素化是否参与了 EGFR 驱动的肿瘤发生。在本研究中，我们鉴定了一种以前未被识别的致癌长非编码 RNA（lncEPAT），它介导失调的 EGFR 通路与肿瘤发生中的 H2A 去泛素化的整合。lncEPAT 被 EGFR 通路诱导，高水平的 lncEPAT 表达与胶质瘤分级呈正相关，并预测胶质瘤患者的预后不良。质谱分析显示，lncEPAT 特异性地与去泛素化酶 USP16 相互作用。lncEPAT 抑制 USP16 向染色质的募集，从而阻断 USP16 介导的 H2A 去泛素化，并抑制靶基因的表达，包括 和 。lncEPAT 的耗竭促进了 USP16 诱导的细胞周期停滞和细胞衰老，从而抑制了 GBM 细胞的肿瘤发生。因此，EGFR-lncEPAT-ubH2A 偶联代表了一种以前未被识别的表观遗传基因调控和 GBM 肿瘤发生过程中衰老抵抗的机制。
