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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number92
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
StatePublished - Jun 19 2019

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Colorectal Neoplasms
Protein Domains
Cell Line
Neoplasms
Transcription Factors
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Expression
Mutation
Chromatin Assembly and Disassembly
MAP Kinase Signaling System
Epigenomics
DNA Damage
Adenocarcinoma
Down-Regulation
Genome

Keywords

  • AP1
  • ARID1A
  • BAF complex
  • Colorectal cancer
  • Enhancers
  • KRAS
  • MEK/ERK pathway
  • Transcriptional regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells. / Sen, Madhobi; Wang, Xin; Hamdan, Feda H.; Rapp, Jacobe; Eggert, Jessica; Kosinsky, Robyn Laura; Wegwitz, Florian; Kutschat, Ana Patricia; Younesi, Fereshteh S.; Gaedcke, Jochen; Grade, Marian; Hessmann, Elisabeth; Papantonis, Argyris; Stróbel, Philipp; Johnsen, Steven.

In: Clinical Epigenetics, Vol. 11, No. 1, 92, 19.06.2019.

Research output: Contribution to journalArticle

Sen, M, Wang, X, Hamdan, FH, Rapp, J, Eggert, J, Kosinsky, RL, Wegwitz, F, Kutschat, AP, Younesi, FS, Gaedcke, J, Grade, M, Hessmann, E, Papantonis, A, Stróbel, P & Johnsen, S 2019, 'ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells', Clinical Epigenetics, vol. 11, no. 1, 92. https://doi.org/10.1186/s13148-019-0690-5
Sen, Madhobi ; Wang, Xin ; Hamdan, Feda H. ; Rapp, Jacobe ; Eggert, Jessica ; Kosinsky, Robyn Laura ; Wegwitz, Florian ; Kutschat, Ana Patricia ; Younesi, Fereshteh S. ; Gaedcke, Jochen ; Grade, Marian ; Hessmann, Elisabeth ; Papantonis, Argyris ; Stróbel, Philipp ; Johnsen, Steven. / ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells. In: Clinical Epigenetics. 2019 ; Vol. 11, No. 1.
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abstract = "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.",
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T1 - ARID1A facilitates KRAS signaling-regulated enhancer activity in an AP1-dependent manner in colorectal cancer cells

AU - Sen, Madhobi

AU - Wang, Xin

AU - Hamdan, Feda H.

AU - Rapp, Jacobe

AU - Eggert, Jessica

AU - Kosinsky, Robyn Laura

AU - Wegwitz, Florian

AU - Kutschat, Ana Patricia

AU - Younesi, Fereshteh S.

AU - Gaedcke, Jochen

AU - Grade, Marian

AU - Hessmann, Elisabeth

AU - Papantonis, Argyris

AU - Stróbel, Philipp

AU - Johnsen, Steven

PY - 2019/6/19

Y1 - 2019/6/19

N2 - 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.

AB - 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.

KW - AP1

KW - ARID1A

KW - BAF complex

KW - Colorectal cancer

KW - Enhancers

KW - KRAS

KW - MEK/ERK pathway

KW - Transcriptional regulation

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