1. Cancer Biology
Download icon

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
Research Article
  • Cited 2
  • Views 1,614
  • Annotations
Cite this article as: eLife 2020;9:e57189 doi: 10.7554/eLife.57189

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

  • 1,614
    Page views
  • 167
    Downloads
  • 2
    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)

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

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

Further reading

    1. Cancer Biology
    2. Medicine
    Maria Ochoa de Olza
    Insight

    Organ-on-chip approaches could help researchers to better predict the toxicity of cancer immunotherapy drugs.

    1. Cancer Biology
    2. Cell Biology
    Brian Spurlock et al.
    Short Report

    Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks'; level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.