Journal Article

ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells

Rapp, Jacobe, Johnsen, Steven A., Gaedcke, Jochen, Wang, Xin, Hessmann, Elisabeth, Papantonis, Argyris, Kosinsky, Robyn Laura, Sen, Madhobi, Eggert, Jessica, Hamdan, Feda H., Strӧbel, Philipp, Grade, Marian, Wegwitz, Florian, Younesi, Fereshteh S., Kutschat, Ana Patricia

2019

Overview

Background ARID1A (AT-rich interactive domain-containing protein 1A) is a subunit of the BAF chromatin remodeling complex and plays roles in transcriptional regulation and DNA damage response. Mutations in ARID1A that lead to inactivation or loss of expression are frequent and widespread across many cancer types including colorectal cancer (CRC). A tumor suppressor role of ARID1A has been established in a number of tumor types including CRC where the genetic inactivation of Arid1a alone led to the formation of invasive colorectal adenocarcinomas in mice. Mechanistically, ARID1A has been described to largely function through the regulation of enhancer activity. Methods To mimic ARID1A-deficient colorectal cancer, we used CRISPR/Cas9-mediated gene editing to inactivate the ARID1A gene in established colorectal cancer cell lines. We integrated gene expression analyses with genome-wide ARID1A occupancy and epigenomic mapping data to decipher ARID1A-dependent transcriptional regulatory mechanisms. Results Interestingly, we found that CRC cell lines harboring KRAS mutations are critically dependent on ARID1A function. In the absence of ARID1A, proliferation of these cell lines is severely impaired, suggesting an essential role for ARID1A in this context. Mechanistically, we showed that ARID1A acts as a co-factor at enhancers occupied by AP1 transcription factors acting downstream of the MEK/ERK pathway. Consistently, loss of ARID1A led to a disruption of KRAS/AP1-dependent enhancer activity, accompanied by a downregulation of expression of the associated target genes. Conclusions We identify a previously unknown context-dependent tumor-supporting function of ARID1A in CRC downstream of KRAS signaling. Upon the loss of ARID1A in KRAS -mutated cells, enhancers that are co-occupied by ARID1A and the AP1 transcription factors become inactive, thereby leading to decreased target gene expression. Thus, targeting of the BAF complex in KRAS -mutated CRC may offer a unique, previously unknown, context-dependent therapeutic option in CRC.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Activator protein 1 / Analysis / Binding sites / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer cells / Cancer epigenetics and diagnostics / Cell Proliferation / Chromatin / Chromatin remodeling / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / CRISPR / CRISPR-Cas Systems / Deoxyribonucleic acid / DNA / DNA binding proteins / DNA damage / DNA Methylation / DNA repair / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enhancer Elements, Genetic / Enhancers / Epigenetics / Gene Editing / Gene expression / Gene Expression Regulation, Neoplastic / Gene Function / Gene mapping / Gene regulation / Genes / Genetic research / Genome editing / Genome-Wide Association Study / Genomes / Genomics / HCT116 Cells / HT29 Cells / Human Genetics / Humans / Invasiveness / K-Ras protein / MAP Kinase Signaling System / Metabolic pathways / Mutation / Occupancy / Phosphorylation / Protein expression / Proteins / Proto-Oncogene Proteins p21(ras) - genetics / Signal Transduction / Transcription (Genetics) / Transcription Factor AP-1 - genetics / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor cell lines / Tumor suppressor genes / Tumors