Critical role of lncEPAT in coupling dysregulated EGFR pathway and histone H2A deubiquitination during glioblastoma tumorigenesis-Reference-Cited by-同舟云学术

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

Published:2022-10-07 Issue:40 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Li Linlin¹^ORCID,Zhou Aidong²^ORCID,Wei Yanjun³^ORCID,Liu Feng⁴,Li Peng¹,Fang Runping¹^ORCID,Ma Li²^ORCID,Zhang Sicong⁵,Wang Longqiang²,Liu Jinze⁶⁷,Richard Hope T.⁷⁸^ORCID,Chen Yiwen³⁹^ORCID,Wang Hengbin⁷¹⁰,Huang Suyun¹⁷¹¹^ORCID

Affiliation:

1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

2. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

3. Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

4. Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.

5. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York City, NY 10065, USA.

6. Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

7. VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

8. Department of Pathology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

9. Quantitative Sciences Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.

10. Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

11. Virginia Commonwealth University Institute of Molecular Medicine, Richmond, VA 23298, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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