Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

Kim, Minchul; Lu, Falong; Zhang, Yi

doi:10.1016/j.celrep.2016.09.003

Cited by 36 publications

(22 citation statements)

References 53 publications

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“…Similarly, promoter accessibility is regulated by the BRG1 and SNF subunits of SWI/SNF (Tolstorukov et al, 2013), but is not affected by ARID1A according to our ATAC-seq analysis. Coherently, a previous DNAse-seq study suggested that very limited changes in hypersensitive sites occurred in ARID1A KO ovarian cells (Kim et al, 2016), however, MNAse-seq studies in mouse ES cells yielded different results (Lei et al, 2015). It is possible that ARID1A contributes to nucleosome remodeling in embryonic stem cells but not in somatic cells.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

et al. 2018

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Summary AT-rich interactive domain-containing protein 1A and 1B (ARID1A, ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (~57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive. Here, we demonstrate that in OCCC ARID1A binds active regulatory elements. Depletion of ARID1A represses RNA Polymerase II (RNAPII) transcription, but results in modest changes to accessibility. Specifically, pausing of RNAPII is severely impaired after loss of ARID1A. Compromised pausing results in transcriptional dysregulation of active genes, which is compensated by upregulation of ARID1B. However, a subset of ARID1A-dependent genes is not rescued by ARID1B, including many p53 and estrogen receptor (ESR1) targets. Our results provide new insight on ARID1A-mediated tumorigenesis and unveil new functions of SWI/SNF in modulating RNAPII dynamics.

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Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

et al. 2018

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“…It is of interest to note that elevated levels of gonadotropins are detected during post-menopause, when OC frequency rises (https://www.cancer.org/ cancer/ovarian-cancer/causes-risks-prevention/riskfactors.html, Webb & Jordan 2017). Therefore, such physiological age-dependent modifications could contribute to determine conditions that, concomitantly with the presence of mutations/deletions of specific genes, facilitate OC onset (Corney et al 2008, Bast et al 2009, Kim et al 2016.…”

Section: Discussionmentioning

confidence: 99%

Increased rounds of gonadotropin stimulation have side effects on mouse fallopian tubes and oocytes

Nisio¹,

Rossi²,

Palmerini³

et al. 2018

Reproduction

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In this study, it was evaluated if increased rounds of gonadotropin stimulation could affect in mice: (i) expression levels of proteins regulating cell cycle and DNA repair in fallopian tubes and (ii) meiotic spindle morphology of ovulated oocytes. To this end, adult female mice were subjected or not (Control) to 6 or 8 rounds of gonadotropin stimulation. Ovulated oocytes were incubated with anti A/B tubulin to evaluate spindle morphology. Fallopian tubes were analyzed to detect Cyclin D1, phospho-p53/p53, phospho-AKT/AKT, phospho-GSK3B/GSK3B, SOX2, OCT3/4, phospho-B-catenin/B-catenin, phospho-CHK1 and phospho-H2A.X protein levels. After 6 rounds, Cyclin D1, p53 and phospho-p53 contents were higher than Control. After 8 rounds, the contents of phosphorylated AKT, GSK3B and p53 as well as of total p53, Cyclin D1 and OCT3/4 significantly increased in comparison with Control. Conversely, SOX2 and B-catenin were similarly expressed among all experimental groups. The finding that phospho-CHK1 and phospho-H2A.X protein levels were undetectable supported the absence of extensive DNA damage. Oocytes number and percentage of normal meiotic spindles drastically decreased from 6 rounds onward. Altogether, our results demonstrated that 6 and 8 cycles of gonadotropin stimulation reduce mouse reproductive performances by inducing over-expression and over-activation of proteins controlling cell cycle progression in fallopian tubes and by impairing oocyte spindle.

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“…Particularly, the group noted minimal alteration of H3K27ac enrichment at promoters and a significant diminishing of H3K27ac levels at enhancers in the absence of ARID1A correlating with reduced mRNA levels of the nearest genes. ARID1A is known to function at both promoters and enhancers, and SWI/SNF complex members have been found to interact with both histone acetyltransferases (HATs) and histone deacetylases (HDACs) [50–52]. Accordingly, we noted that over 60% of promoters and nearly 25% of enhancers were altered in H3K27ac enrichment upon loss of ARID1A, and some of these histone changes translated to stark corresponding alterations in chromatin accessibility, and likely gene expression, as the majority of the differentially expressed genes showed correlative histone mark alterations.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells

et al. 2017

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The chromatin remodeler AT-Rich Interactive Domain 1A (ARID1A) is frequently mutated in ovarian clear cell carcinoma (OCCC) and endometriosis precursor lesions. Here, we show that knocking down ARID1A in an immortalized endometriosis cell line is sufficient to induce phenotypic changes indicative of neoplastic transformation as evidenced by higher efficiency of anchorage-independent growth, increased propensity to adhere to collagen, and greater capacity to invade basement membrane extract in vitro. ARID1A knockdown is associated with expression dysregulation of 99 target genes, and many of these expression changes are also observed in primary OCCC tissues. Further, pathway analysis indicates these genes fall within networks highly relevant to tumorigenesis including integrin and paxillin pathways. We demonstrate that the down-regulation of ARID1A does not markedly alter global chromatin accessibility or DNA methylation but unexpectedly, we find strong increases in the active H3K27ac mark in promoter regions and decreases of H3K27ac at potential enhancers. Taken together, these data provide evidence that ARID1A mutation can be an early stage event in the oncogenic transformation of endometriosis cells giving rise to OCCC.

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Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

Cited by 36 publications

References 53 publications

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

Increased rounds of gonadotropin stimulation have side effects on mouse fallopian tubes and oocytes

Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells

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