Low DUSP4 Expression Is Associated With Aggressive Phenotypes and Poor Prognosis in Gastric Cancer

Bang, Seongsik; Jee, Seungyun; Kim, Hyunsung; Jang, Kiseok; Park, Hosub; Myung, Jae Kyung; Choi, Dongho; Shin, Su Jin; Paik, Seung Sam

doi:10.21873/invivo.12240

Cited by 5 publications

(2 citation statements)

References 27 publications

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“…The involvement of ARID1A in tumorigenesis through transcriptional reprogramming is well established in the literature [ 15 ], yet our research uniquely emphasizes its role in modulating MAPK pathway activation. Our findings align with previous studieshighlighting the importance of tumor suppressor function of DUSP4 in human malignancies [ 30 , 32 , 33 , 35 ]. Although DUSP4 expression can be detected in patients with various malignancies, including endometrial cancer, its levels decrease in more advanced stages of the disease, suggesting that the MAPK pathway is activated in patients in advanced cancer stages.…”

Section: Discussionsupporting

confidence: 93%

“…One such negative regulator of the MAPK pathway is DUSP4, which induces the dephosphorylation of members belonging to the MAPK pathway [ 29 – 31 ]. Also referred to as mitogen-activated protein kinase phosphatase 2 (MKP-2), its low expression or downregulation is linked to aggressive tumor phenotypes, metastasis, and poor prognosis [ 32 – 34 ] [ 35 ], and an enhancer of chemotherapy efficacy [ 36 – 38 ]. Despite its importance, the role of DUSP4 has not been extensively studied in gynecologic cancer, especially in those with ARID1A mutations.…”

Section: Introductionmentioning

confidence: 99%

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ARID1A loss activates MAPK signaling via DUSP4 downregulation

Mandal,

Yu,

Shih

et al. 2023

J Biomed Sci

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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.

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