Journal Article

Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to oesophageal adenocarcinoma

Sharrocks, Andrew D, Ogden, Samuel, Britton, Edward, Ang, Yeng, Rogerson, Connor

2020

Overview

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. Acid fluids present in the gut can sometimes ‘go up’ and damage the oesophagus, the pipe that connects the mouth and the stomach. As a result, a small number of individuals can develop Barrett’s oesophagus, a condition where cells in the lining of the lower oesophagus show abnormal shapes. In certain patients, these cells then become cancerous, but exactly how this happens is unknown. This lack of understanding contributes to late diagnoses, limited treatment and low survival rates. Many cancers feature ‘signature’ mutations in a set of genes that controls how a cell can multiply. Yet, in the case of cancers of the lower oesophagus, known genetic changes have had a limited impact on our understanding of the emergence of the disease. Here, Rogerson et al. focused instead on non-genetic changes and studied transcription factors, the proteins that bind to regulatory regions of the DNA to switch genes on and off. A close inspection of cancer cells in the lower oesophagus revealed that, in that state, a transcription factor called KLF5 controls the abnormal activation of genes involved in cell growth. This is linked to the transcription factor adopting a different pattern of binding onto regulatory regions in diseased cells. Crucially, when the cell growth genes regulated by KLF5 are activated, patients have lower survival rates. Further work is now required to examine whether this finding could help to identify patients who are most at risk from developing cancer. More broadly, the results from the work by Rogerson et al. demonstrate how transcription factors can be repurposed in a disease context.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Barrett Esophagus - genetics / Barrett Esophagus - pathology / Cancer Biology / Cell cycle / Cell Cycle - genetics / Cell Line, Tumor / Chromatin / Comparative analysis / Development and progression / DNA binding proteins / Esophageal cancer / Esophageal Neoplasms - genetics / Esophageal Neoplasms - pathology / Genes / Health aspects / Humans / KLF5 / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - metabolism / oesophageal cancer / Protein binding / Transcription (Genetics) / transcription factors