Critical role of lncEPAT in coupling dysregulated EGFR pathway and histone H2A deubiquitination during glioblastoma tumorigenesis
Menée à l'aide de lignées cellulaires, d'échantillons tumoraux d'origine humaine et d'un modèle murin de glioblastome, cette étude met en évidence un mécanisme par lequel le long ARN non codant lncEPAT, induit par la voie de signalisation du récepteur EGFR, favorise la tumorigenèse en bloquant la déubiquitination de l'histone 2A par la déubiquitinase UPS16
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 CDKN1A and CLUSTERIN. 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. LncEPAT induced by EGFR activation in glioma cells inhibited tumor cell senescence and promoted glioblastoma tumorigenesis.
Science Advances 2022