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

Abstract
Data availability
Article and author information
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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

(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExpress, E-MTAB-8447.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8447
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExpress, E-MTAB-8446.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8446
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExpress, E-MTAB-8568.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8568
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExpress, E-MTAB-8584.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8584
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExpress, E-MTAB-8576.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8576
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExpress, E-MTAB-8579.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8579
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
EGA, EGAD00001005915.

https://ega-archive.org/datasets/EGAD00001005915
(2020) Repurposing of KLF5 activates a cell cycle signature during the progression to Oesophageal Adenocarcinoma
ArrayExoress, E-MTAB-8994.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8994

The following previously published data sets were used

1. Britton E
2. Rogerson C
3. Mehta S
4. Li Y
5. Li X
6. the OCCAMS consortium
7. Fitzgerald RC
8. Ang YS
9. Sharrocks AD
(2017) Open chromatin profiling identifies AP1 as a transcriptional regulator in oesophageal adenocarcinoma
ArrayExpress, E-MTAB-5169.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5169
1. Rogerson C
2. Britton E
3. Withey S
4. Hanley N
5. Ang Y
6. Sharrocks AD
(2019) Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its pre-cancerous precursor state
ArrayExpress, E-MTAB-6751.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6751
1. Rogerson C
2. Britton E
3. Withey S
4. Hanley N
5. Ang Y
6. Sharrocks AD
(2019) Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its pre-cancerous precursor state
ArrayExpress, E-MTAB-6756.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6756
1. Rogerson C
2. Britton E
3. Withey S
4. Hanley N
5. Ang Y
6. Sharrocks AD
(2019) Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its pre-cancerous precursor state
ArrayExpress, E-MTAB-6758.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6858
1. Maag JLV
2. Fisher OM
3. Levert-Mignon A
4. Kaczorowski DC
5. Thomas ML
6. Hussey DJ
7. Watson DI
8. Wettstein A
9. Bobryshev YV
10. Edwards M
11. Dinger ME
12. Lord RV
(2017) Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing
ArrayExpress, E-MTAB-4054.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-4054
1. Corces MR
2. Granja JM
3. Shams S
4. Louie BH
5. Seoane
6. JA
7. Zhou W
8. Silva TC
9. Groeneveld C
10. Wong CK
11. Cho SW
12. Satpathy AT
13. Mumbach MR
14. Hoadley KA
15. Robertson AG
16. Sheffield NC
17. Felau I
18. Castro MAA
19. Berman BP
20. Staudt LM
21. Zenklusen JC
22. Laird PW
23. Curtis C
24. TCGA Network
25. Greenleaf WJ
26. Chang HY
(2018) The chromatin accessibility landscape of primary human cancers
GDC Data Portal, TCGA-ESCA.

https://portal.gdc.cancer.gov/projects/TCGA-ESCA

Article and author information

Author details

Connor Rogerson

Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1425-9668
Samuel Ogden

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Edward Britton

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Competing interests
The authors declare that no competing interests exist.
the OCCAMS consortium
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.

"This ORCID iD identifies the author of this article:" 0000-0003-0496-6710
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.

"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.

Copyright

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.