Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer

EMBO J. 2016 Mar 15;35(6):595-617. doi: 10.15252/embj.201592404. Epub 2016 Jan 14.

Abstract

The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high- and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low-grade primary PDACs and cell lines, where it maintained the acetylation of grade-specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression.

Keywords: differentiation; enhancers; epigenetics; epithelial–mesenchymal transition; pancreatic ductal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genetic Markers
  • Humans
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • Genetic Markers
  • Transcription Factors