Open AccessGenome-Wide Analysis of the FOXA1 Transcriptional Network Identifies Novel Protein-Coding and Long Noncoding RNA Targets in Colorectal Cancer Cells
Author(s) -
Sarah B. Lazar,
Lőrinc Sándor Pongor,
Xiao Ling Li,
Ioannis Grammatikakis,
Bruna Rodrigues Muys,
Emily A. Dangelmaier,
Christophe E. Redon,
SangMin Jang,
Robert L. Walker,
Wei Tang,
Stefan Ambs,
Curtis C. Harris,
Paul S. Meltzer,
Mirit I. Aladjem,
Ashish Lal
Publication year - 2020
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00224-20
Subject(s) - foxa1 , biology , transcription factor , cancer research , gene knockdown , chromatin immunoprecipitation , chromatin , enhancer , genetics , gene , gene expression , promoter
Differentiation status of tumors is correlated with metastatic potential and malignancy. FOXA1 (forkhead box A1) is a transcription factor known to regulate differentiation in certain tissues. Here, we investigate FOXA1 function in human colorectal cancer (CRC). We found that FOXA1 is robustly expressed in the normal human colon but significantly downregulated in colon adenocarcinoma. Applying FOXA1 chromatin immunoprecipitation coupled with deep sequencing and transcriptome analysis upon FOXA1 knockdown in well-differentiated CRC cells and FOXA1 overexpression in poorly differentiated CRC cells, we identified novel protein-coding and lncRNA genes regulated by FOXA1. Among the numerous novel FOXA1 targets we identified, we focused on CEACAM5 , a tumor marker and facilitator of cell adhesion. We show that FOXA1 binds to a distal enhancer downstream of CEACAM5 and strongly activates its expression. Consistent with these data, we show that FOXA1 inhibits anoikis in CRC cells. Collectively, our results uncover novel protein-coding and noncoding targets of FOXA1 and suggest a vital role of FOXA1 in enhancing CEACAM5 expression and anoikis resistance in CRC cells.