Critical role of lncEPAT in coupling dysregulated EGFR pathway and histone H2A deubiquitination during glioblastoma tumorigenesis.

Abstract

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.

• Authors: Linlin Li, Aidong Zhou, Yanjun Wei, Feng Liu, Peng Li, Runping Fang, Li Ma, Sicong Zhang, Longqiang Wang, Jinze Liu, Hope T Richard, Yiwen Chen, Hengbin Wang, Suyun Huang
• Journal: Science advances (Sci Adv) Vol. 8 Issue 40 Pg. eabn2571 (10 07 2022) ISSN: 2375-2548 [Electronic] United States
• PMID: 36197973 (Publication Type: Journal Article)

Chemical References

• Chromatin
• Clusterin
• Histones
• RNA, Long Noncoding
• EGFR protein, human
• ErbB Receptors
• Ubiquitin Thiolesterase

Topics

• Carcinogenesis (genetics)
• Chromatin
• Clusterin (metabolism)
• ErbB Receptors (genetics)
• Glioblastoma (genetics)
• Histones (metabolism)
• Humans
• RNA, Long Noncoding
• Ubiquitin Thiolesterase (genetics)