ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

Wilson, Mike R.; Reske, Jake J.; Holladay, Jeanne; Neupane, Subechhya; Ngo, Julie; Cuthrell, Nina; Wegener, Marc; Rhodes, Mary; Adams, Marie; Sheridan, Rachael; Hostetter, Galen; Alotaibi, Fahad T; Yong, Paul J.; Anglesio, Michael S.; Lessey, Bruce A.; Leach, Richard E.; Teixeira, Jose; Missmer, Stacey A.; Fazleabas, Asgerally T.; Chandler, Ronald L.

doi:10.1016/j.celrep.2020.108366

Cited by 49 publications

(66 citation statements)

References 120 publications

(157 reference statements)

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“…We have previously shown that ARID1A normally represses key genes involved in endometrial pathologies through chromatin mechanisms [34,50]. We hypothesized that p53 pathway activation following ARID1A loss could result from the derepression of ARID1A target genes.…”

Section: P53 Pathway Target Genes Are Directly Regulated By Arid1amentioning

confidence: 98%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

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TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

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Section: P53 Pathway Target Genes Are Directly Regulated By Arid1amentioning

confidence: 98%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

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“…There remains work to be done in this area in the future, including detailed and comprehensive analysis of chromatin accessibility changes after loss of Arid1a in the mouse incisor and identification of co-factors working with Arid1a to control cell cycle progression. Several recent studies reported the emerging role of ARID1A in regulating enhancer-mediated gene expression in human colorectal cancer (Mathur et al, 2017) and neuroblastoma cells (Shi et al, 2020) and in preventing superenhancer hyperactivation in endometrial epithelia (Wilson et al, 2020). These findings highlight the importance of Arid1a in homeostasis of multiple tissues as well as the context-dependent character of its function.…”

Section: Discussionmentioning

confidence: 85%

Arid1a regulates cell cycle exit of transit-amplifying cells by inhibiting the Aurka-Cdk1 axis in mouse incisor

Jing

Chen

et al. 2021

Development

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Stem cells self-renew or give rise to transit-amplifying cells (TACs) that differentiate into specific functional cell types. The fate determination of stem cells to TACs and their transition to fully differentiated progeny are precisely regulated to maintain tissue homeostasis. Arid1a, a core component of the switch/sucrose nonfermentable (SWI/SNF) complex, performs epigenetic regulation of stage- and tissue-specific genes that is indispensable for stem cell homeostasis and differentiation. However, the functional mechanism of Arid1a in the fate commitment of mesenchymal stem cells (MSCs) and their progeny is not clear. Using the continuously growing adult mouse incisor model, we show that Arid1a maintains tissue homeostasis through limiting proliferation, promoting cell cycle exit and differentiation of TACs by inhibiting the Aurka-Cdk1 axis. Loss of Arid1a overactivates the Aurka-Cdk1 axis, leading to expansion of the mitotic TAC population but compromising their differentiation ability. Furthermore, the defective homeostasis after loss of Arid1a ultimately leads to reduction of the MSC population. These findings reveal the functional significance of Arid1a in regulating the fate of TACs and their interaction with MSCs to maintain tissue homeostasis.

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“…In addition, another study demonstrated that alterations in both the ARID1A and PI3-Kinase (PI3K) pathways promote epithelial trans-differentiation and invasion [45]. The epigenetic role of ARID1A was also revealed in a pre-OCCC model system: ARID1A prevents superenhancer hyperactivation, which leads to enhanced migratory properties exhibited by pre-OCCC cells [46]. In addition, a common role shared by ARID1A and another SWI/SNF factor, SMARCA4/BRG1, maintains the integrity of the endometrial epithelium [47].…”

Section: Arid1a and Other Swi/snf Gene Alterations In Occcmentioning

confidence: 99%

Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma

Takahashi

Takenaka

Okamoto

et al. 2021

Cancers

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Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.

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ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

Cited by 49 publications

References 120 publications

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

Arid1a regulates cell cycle exit of transit-amplifying cells by inhibiting the Aurka-Cdk1 axis in mouse incisor

Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma

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