Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

  1. Connor Rogerson
  2. Samuel Ogden
  3. Edward Britton
  4. the OCCAMS consortium
  5. Yeng Ang  Is a corresponding author
  6. Andrew D Sharrocks  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Manchester, United Kingdom

Abstract

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett's oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.

Data availability

All sequencing data are deposited in ArrayExpress. Additional OAC ATAC-seq data are available at E-MTAB-8447 and additional BO and OAC RNA-seq data are available at E-MTAB-8584. siKLF5 RNA-seq data are available at E-MTAB-8446. KLF5 ChIP-seq data are available at E-MTAB-8568. siERBB2 ATAC-seq and RNA-seq data are available at E-MTAB-8576 and E-MTAB-8579 respectively.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Connor Rogerson

    Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1425-9668
  2. Samuel Ogden

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Edward Britton

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. the OCCAMS consortium

  5. Yeng Ang

    School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    For correspondence
    Yeng.Ang@srft.nhs.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0496-6710
  6. Andrew D Sharrocks

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    For correspondence
    andrew.d.sharrocks@manchester.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7395-9552

Funding

Cancer Research UK (Clinical PhD and PhD funding)

  • Connor Rogerson
  • Edward Britton
  • Yeng Ang
  • Andrew D Sharrocks

Wellcome (Programme grant and studentship103857/Z/14/Z)

  • Samuel Ogden
  • Andrew D Sharrocks

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

Ethics

Human subjects: Ethical approval was via the ethics committee of Salford Royal NHS Foundation Trust (04/Q1410/57). Patient consent was obtained in written form and signed by the patient and doctor.

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Publication history

  1. Received: March 24, 2020
  2. Accepted: September 3, 2020
  3. Accepted Manuscript published: September 3, 2020 (version 1)
  4. Version of Record published: October 8, 2020 (version 2)

Copyright

© 2020, Rogerson 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

  • 2,065
    Page views
  • 200
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Connor Rogerson
  2. Samuel Ogden
  3. Edward Britton
  4. the OCCAMS consortium
  5. Yeng Ang
  6. Andrew D Sharrocks
(2020)
Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma
eLife 9:e57189.
https://doi.org/10.7554/eLife.57189

Further reading

    1. Cancer Biology
    2. Chromosomes and Gene Expression
    Arnaud Carrier, Cécile Desjobert ... Paola B Arimondo
    Research Article

    Aberrant DNA methylation is a well‑known feature of tumours and has been associated with metastatic melanoma. However, since melanoma cells are highly heterogeneous, it has been challenging to use affected genes to predict tumour aggressiveness, metastatic evolution, and patients' outcomes. We hypothesized that common aggressive hypermethylation signatures should emerge early in tumorigenesis and should be shared in aggressive cells, independent of the physiological context under which this trait arises. We compared paired melanoma cell lines with the following properties: (i) each pair comprises one aggressive counterpart and its parental cell line, and (ii) the aggressive cell lines were each obtained from different host and their environment (human, rat, and mouse), though starting from the same parent cell line. Next, we developed a multi-step genomic pipeline that combines the DNA methylome profile with a chromosome cluster-oriented analysis. A total of 229 differentially hypermethylated genes were commonly found in the aggressive cell lines. Genome localization analysis revealed hypermethylation peaks and clusters, identifying eight hypermethylated gene promoters for validation in tissues from melanoma patients. Five CpG identified in primary melanoma tissues were transformed into a DNA methylation score that can predict survival (Log-rank test, p=0.0008). This strategy is potentially universally applicable to other diseases involving DNA methylation alterations.

    1. Cancer Biology
    2. Immunology and Inflammation
    Amit Gutwillig, Nadine Santana-Magal ... Yaron Carmi
    Research Article

    Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhibiting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity.