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ARID1A loss activates MAPK signaling via DUSP4 downregulation
Jayaprakash Mandal1,2,3, Zheng-Cheng Yu1,2,3, Ie-Ming Shih4,5,6
1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Background:
ARID1A, a tumor suppressor gene encoding BAF250, a protein participating in chromatin remodeling, is frequently mutated in endometrium-related malignancies, including ovarian or uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). However, how ARID1A mutations alter downstream signaling to promote tumor development is yet to be established.
Methods:
We used RNA-sequencing (RNA-seq) to explore transcriptomic changes in isogenic human endometrial epithelial cells after deleting ARID1A. Chromatin immunoprecipitation sequencing (ChIP-seq) was employed to assess the active or repressive histone marks on DUSP4 promoter and regulatory regions. We validated our findings using genetically engineered murine endometroid carcinoma models, human endometroid carcinoma tissues, and in silico approaches.
Results:
RNA-seq revealed the downregulation of the MAPK phosphatase dual-specificity phosphatase 4 (DUSP4) in ARID1A-deficient cells. ChIP-seq demonstrated decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 regulatory regions as one of the causes for DUSP4 downregulation in ARID1A-deficient cells. Ectopic DUSP4 expression decreased cell proliferation, and pharmacologically inhibiting the MAPK pathway significantly mitigated tumor formation in vivo.
Conclusions:
Our findings suggest that ARID1A protein transcriptionally modulates DUSP4 expression by remodeling chromatin, subsequently inactivating the MAPK pathway, leading to tumor suppression. The ARID1A-DUSP4-MAPK axis may be further considered for developing targeted therapies against ARID1A-mutated cancers.
Insights
ARID1A mutations reduce DUSP4 expression by altering chromatin, which inactivates the MAPK pathway and promotes tumor growth. Targeting this ARID1A-DUSP4-MAPK axis may treat ARID1A-mutated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- ARID1A, a tumor suppressor gene, is frequently mutated in endometrial cancers.
- The downstream effects of ARID1A mutations in tumor development are not fully understood.
Purpose of the Study:
- To investigate how ARID1A mutations influence downstream signaling pathways in endometrial cancer.
- To identify potential therapeutic targets for ARID1A-mutated malignancies.
Main Methods:
- RNA-sequencing to analyze transcriptomic changes in ARID1A-deficient cells.
- Chromatin immunoprecipitation sequencing to assess histone modifications on the DUSP4 promoter.
- Validation in murine models, human tissues, and in silico approaches.
Main Results:
- ARID1A deficiency led to downregulation of dual-specificity phosphatase 4 (DUSP4).
- Decreased histone acetylation on DUSP4 regulatory regions contributed to its reduced expression.
- Restoring DUSP4 expression inhibited cell proliferation, and MAPK pathway inhibition reduced tumor formation.
Conclusions:
- ARID1A protein regulates DUSP4 expression via chromatin remodeling, impacting the MAPK pathway.
- The ARID1A-DUSP4-MAPK signaling axis is a potential therapeutic target for ARID1A-mutated cancers.
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