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Loss of HDAC-mediated repression and gain of NF-kB activation underlies cytokine induction in ARID1A and PIK3CA mutation-driven ovarian cancer

ABSTRACT: ARID1A is frequently mutated in ovarian clear-cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here we established an in vitro model of OCCC by introducing ARID1A knock-down and mutant PIK3CA in a normal human ovarian epithelial cell line, which resulted in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while PIK3CA mutation releases RelA from IkB, leading to cytokine gene activation. We show that an NF-kB inhibitor partly attenuates proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC, and suggests NF-kB inhibition can be a potential therapeutic option.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86004 | GEO | 2016/09/15

SECONDARY ACCESSION(S): PRJNA339979

REPOSITORIES: GEO

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Coexistent ARID1A-PIK3CA mutations promote ovarian clear cell tumorigenesis through pro-tumorigenic inflammatory cytokine signaling

Project description:Ovarian clear cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a genetically engineered mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolonged mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A-PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis.

2014-12-31 | GSE57380 | GEO

PPP2R1A mutations cause ATR inhibitor synthetic lethality in ARID1A deficient ovarian clear cell carcinoma

Project description:Ovarian clear cell carcinoma (OCCC) is a cancer of unmet need characterized by ARID1A mutation. Prior work identified an ARID1A/ATR synthetic lethality, information that led to phase II clinical trials. Using genome-wide CRISPR-Cas9 mutagenesis and interference screens, we identified protein phosphatase 2A (PP2A) subunits, including PPP2R1A, as determinants of ATRi sensitivity in ARID1A mutant OCCC. Analysis of an OCCCs cohort indicated that >1/3 possessed both PPP2R1A and ARID1A loss-of-function mutations. CRISPR-prime editing demonstrated that oncogenic PPP2R1A p.R183 missense mutations enhance in vitro and in vivo ATRi sensitivity in ARID1A mutant OCCC. OCCC patients with both ARID1A and PPP2R1A mutations also showed clinical responses to ATRi in a phase II trial. Mechanistically, this synthetic lethal effect is dependent upon WNK1 kinase, which opposes PP2A function. This data suggests that co-occurrence of PPP2R1A and ARID1A mutations in OCCC should be assessed as a biomarker of ATRi response in on-going clinical trials.

2023-05-10 | PXD040422 | Pride

Homo sapiens

Project description:Loss of HDAC-mediated repression and gain of NF-kB activation underlies cytokine induction in ARID1A and PIK3CA mutation-driven ovarian cancer

| PRJNA339979 | ENA

Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C (Affymetrix)

Project description:Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology. Copy number variation was determined for multiple Ovarian Clear Cell Carcinomas

2020-11-01 | GSE160569 | GEO

Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C (Oncomine)

2020-11-01 | GSE160570 | GEO

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

2015-01-20 | GSE54979 | GEO

A novel YDDX linear motif mediates docking of the IKK kinase to substrates: structural and functional insights

Project description:The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors. The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.

2024-05-09 | PXD037534 | JPOST Repository

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress

Mus musculus

Project description:Coexistent ARID1A-PIK3CA mutations promote ovarian clear cell tumorigenesis through pro-tumorigenic inflammatory cytokine signaling

| PRJNA246369 | ENA

Oncogenic PI3K mutations lead to NF-kB-dependent cytokine expression following growth

Project description:While growth factor-independent signaling and proliferation are well-established hallmarks of cancer, little is known regarding growth factor-independent changes in gene expression which occur downstream from oncogenes. The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers. Here, MCF10A cells expressing the two most common PI3K mutations, PIK3CA E545K and H1047R, were used to identify the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, and categorical enrichment analyses suggested that NF-kB target genes were dramatically upregulated by these mutations. An IKKb inhibitor was used to identify the subset of PI3K-driven genes that is NF-kB dependent. Interestingly, virtually all of these NF-kB dependent genes were secreted proteins, suggesting a paracrine role for this gene set. Among these genes was IL-6, a cytokine frequently expressed in tumors which plays a critical role in generating a tumor-promoting microenvironment. Consistent with this, conditioned media from cells expressing the E545K or H1047R mutations led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-kB and IL-6-dependent manner. Together, these data describe a PI3K-driven, NF-kB-dependent gene expression profile which may play a critical role in promoting a microenvironment amenable to tumor progression. 39 normal cell lines vs treated cell lines for micorarray analysis

2012-04-30 | E-GEOD-33403 | biostudies-arrayexpress

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