IER5, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation

  1. Li Pan
  2. Madeleine E Lemieux
  3. Tom Thomas
  4. Julia M Rogers
  5. Colin H Lipper
  6. Winston Lee
  7. Carl Johnson
  8. Lynette M Sholl
  9. Andrew P South
  10. Jarrod A Marto
  11. Guillaume O Adelmant
  12. Stephen C Blacklow
  13. Jon C Aster  Is a corresponding author
  1. Brigham and Women's Hospital, United States
  2. Bioinfo, Canada
  3. Harvard Medical School, United States
  4. Thomas Jefferson University, United States
  5. Dana-Farber Cancer Institute, United States
  6. Dana Farber Cancer Institute, United States
  7. Harvard, United States

Abstract

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55a subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE156488 and GSE156624

The following data sets were generated

Article and author information

Author details

  1. Li Pan

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  2. Madeleine E Lemieux

    Bioinfo, Ontario, Canada
    Competing interests
    No competing interests declared.
  3. Tom Thomas

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  4. Julia M Rogers

    Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Colin H Lipper

    Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Winston Lee

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  7. Carl Johnson

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  8. Lynette M Sholl

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  9. Andrew P South

    Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    No competing interests declared.
  10. Jarrod A Marto

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Guillaume O Adelmant

    Oncologic Pathology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Stephen C Blacklow

    Department of Biological Chemistry and Molecular Pharmacology, Harvard, Boston, United States
    Competing interests
    Stephen C Blacklow, SCB is on the SAB for Erasca, Inc., receives sponsored research funding from Novartis and Erasca, Inc, and is a consultant for IFM therapeutics and Ayala Pharmaceuticals..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6904-1981
  13. Jon C Aster

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    For correspondence
    jaster@rics.bwh.harvard.edu
    Competing interests
    Jon C Aster, JCA is a consultant for Ayala Pharmaceuticals and for Cellestia, Inc. There is no conflict of interest with the work described in this manuscript..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1957-9070

Funding

Ludwig Institute for Cancer Research (None)

  • Jon C Aster

National Institutes of Health (R35 CA220340)

  • Stephen C Blacklow

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Pan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,249
    views
  • 234
    downloads
  • 12
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Li Pan
  2. Madeleine E Lemieux
  3. Tom Thomas
  4. Julia M Rogers
  5. Colin H Lipper
  6. Winston Lee
  7. Carl Johnson
  8. Lynette M Sholl
  9. Andrew P South
  10. Jarrod A Marto
  11. Guillaume O Adelmant
  12. Stephen C Blacklow
  13. Jon C Aster
(2020)
IER5, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation
eLife 9:e58081.
https://doi.org/10.7554/eLife.58081

Share this article

https://doi.org/10.7554/eLife.58081

Further reading

    1. Cancer Biology
    Bruno Bockorny, Lakshmi Muthuswamy ... Senthil K Muthuswamy
    Tools and Resources

    Pancreatic cancer has the worst prognosis of all common tumors. Earlier cancer diagnosis could increase survival rates and better assessment of metastatic disease could improve patient care. As such, there is an urgent need to develop biomarkers to diagnose this deadly malignancy. Analyzing circulating extracellular vesicles (cEVs) using ‘liquid biopsies’ offers an attractive approach to diagnose and monitor disease status. However, it is important to differentiate EV-associated proteins enriched in patients with pancreatic ductal adenocarcinoma (PDAC) from those with benign pancreatic diseases such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). To meet this need, we combined the novel EVtrap method for highly efficient isolation of EVs from plasma and conducted proteomics analysis of samples from 124 individuals, including patients with PDAC, benign pancreatic diseases and controls. On average, 912 EV proteins were identified per 100 µL of plasma. EVs containing high levels of PDCD6IP, SERPINA12, and RUVBL2 were associated with PDAC compared to the benign diseases in both discovery and validation cohorts. EVs with PSMB4, RUVBL2, and ANKAR were associated with metastasis, and those with CRP, RALB, and CD55 correlated with poor clinical prognosis. Finally, we validated a seven EV protein PDAC signature against a background of benign pancreatic diseases that yielded an 89% prediction accuracy for the diagnosis of PDAC. To our knowledge, our study represents the largest proteomics profiling of circulating EVs ever conducted in pancreatic cancer and provides a valuable open-source atlas to the scientific community with a comprehensive catalogue of novel cEVs that may assist in the development of biomarkers and improve the outcomes of patients with PDAC.

    1. Cancer Biology
    2. Evolutionary Biology
    Lingjie Zhang, Tong Deng ... Chung-I Wu
    Research Article

    Tumorigenesis, like most complex genetic traits, is driven by the joint actions of many mutations. At the nucleotide level, such mutations are cancer-driving nucleotides (CDNs). The full sets of CDNs are necessary, and perhaps even sufficient, for the understanding and treatment of each cancer patient. Currently, only a small fraction of CDNs is known as most mutations accrued in tumors are not drivers. We now develop the theory of CDNs on the basis that cancer evolution is massively repeated in millions of individuals. Hence, any advantageous mutation should recur frequently and, conversely, any mutation that does not is either a passenger or deleterious mutation. In the TCGA cancer database (sample size n=300–1000), point mutations may recur in i out of n patients. This study explores a wide range of mutation characteristics to determine the limit of recurrences (i*) driven solely by neutral evolution. Since no neutral mutation can reach i*=3, all mutations recurring at i≥3 are CDNs. The theory shows the feasibility of identifying almost all CDNs if n increases to 100,000 for each cancer type. At present, only <10% of CDNs have been identified. When the full sets of CDNs are identified, the evolutionary mechanism of tumorigenesis in each case can be known and, importantly, gene targeted therapy will be far more effective in treatment and robust against drug resistance.