Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer
Manjie Xing, … , Bin Tean Teh, Patrick Tan
Manjie Xing, … , Bin Tean Teh, Patrick Tan
Published May 4, 2020
Citation Information: J Clin Invest. 2020;130(6):3005-3020. https://doi.org/10.1172/JCI126726.
View: Text | PDF
Research Article Gastroenterology Oncology Article has an altmetric score of 3

Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer

  • Text
  • PDF
Abstract

Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA–binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1.

Authors

Manjie Xing, Wen Fong Ooi, Jing Tan, Aditi Qamra, Po-Hsien Lee, Zhimei Li, Chang Xu, Nisha Padmanabhan, Jing Quan Lim, Yu Amanda Guo, Xiaosai Yao, Mandoli Amit, Ley Moy Ng, Taotao Sheng, Jing Wang, Kie Kyon Huang, Chukwuemeka George Anene-Nzelu, Shamaine Wei Ting Ho, Mohana Ray, Lijia Ma, Gregorio Fazzi, Kevin Junliang Lim, Giovani Claresta Wijaya, Shenli Zhang, Tannistha Nandi, Tingdong Yan, Mei Mei Chang, Kakoli Das, Zul Fazreen Adam Isa, Jeanie Wu, Polly Suk Yean Poon, Yue Ning Lam, Joyce Suling Lin, Su Ting Tay, Ming Hui Lee, Angie Lay Keng Tan, Xuewen Ong, Kevin White, Steven George Rozen, Michael Beer, Roger Sik Yin Foo, Heike Irmgard Grabsch, Anders Jacobsen Skanderup, Shang Li, Bin Tean Teh, Patrick Tan

×

Figure 1

EBF1 TF expression is negatively associated with TERT.

Options: View larger image (or click on image) Download as PowerPoint

EBF1 TF expression is negatively associated with TERT.
(A) Expression o...
(A) Expression of TERT in normal gastric (n = 35) and GC samples (n = 415) from TCGA consortium. Q values were determined by Wilcoxon’s rank-sum test with FDR multiple testing correction. RSEM, RNA-Seq by expectation-maximization (https://github.com/deweylab/RSEM). (B) Correlation of mRNA levels between TERT and TFs (ENCODE ChIP-Seq database) at genomic regions flanking the TERT TSS. Correlation coefficients were computed using the normalized expression matrix from TCGA. *Q < 0.05, **Q < 0.01, and ***Q < 0.001, by Pearson’s correlation test with FDR multiple testing correction. (C) A significant negative correlation was found between TERT and EBF1 mRNA levels in the South Korean and Singapore cohorts. Top: microarray data for 96 GC samples from the Korean cohort (median-centered, log-transformed). Bottom: microarray data for 185 GC samples from the Singapore (SG) cohort (log2 expression level). P values were determined by Pearson’s correlation test. (D) Graph shows EBF1 and TERT expression levels based on RNA-Seq data for 63 GC lines. FPKM, fragments per kilobase per million mapped reads. (E) TaqMan qPCR validation of EBF1 expression levels using in-house normal stomach tissues. (F) EBF1 expression levels in normal gastric organoids (microarray). RMA, robust multiarray average. (G) Western blot analysis of EBF1 protein expression in GC lines. Ctrl, control. (H) Expression of EBF1 in normal gastric (n = 35) and GC samples (n = 415) from TCGA. P value was determined by Wilcoxon’s rank sum test. (I) EBF1 immunohistochemistry for GC tissues and normal gastric epithelium. Left: normal gastric epithelium with EBF1 expression (brown); middle: GC cells with EBF1 expression in 15% of the tumor cells (brown); right: intestinal-type GC cells with complete loss of EBF1 expression, endothelial cells and lymphocytes in the tumor stroma were EBF1+ (brown). Original magnification, x40. Red arrows indicate stained cells. (J) Distribution of immunohistochemical scores for EBF1 protein expression in 51 GCs and matched normal tissues, connected by black lines. P value was determined by 2-sided t test. (A and H) For the box-and-whisker plots, the lines within boxes indicate the median, the bounds of the boxes indicate the upper and lower quartiles, the whiskers indicate the minimum and maximum values, and the separated points indicate outliers.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 3 X users
26 readers on Mendeley
See more details