Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERα and growth factors via MAPK pathway

Ounzain, Samir; Bowen, Samantha; Patel, Chandrakant; Fujita, Rieko; Heads, Richard J.; Budhram-Mahadeo, Vishwanie

doi:10.1186/bcr2809

Cited by 13 publications

(20 citation statements)

References 27 publications

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“…This is the first report showing that increased Brn-3b transcription factor may be important for controlling growth and behaviour of human ovarian cancer cells, particularly following treatment with common chemotherapeutic agents such as cisplatin and paclitaxel. These results, when combined with data from studies in other cancer related models [10–14, 18, 27], points to an important role for Brn-3b in promoting survival and drug resistance in ovarian cancer cells. Based on its known function, the effects of Brn-3b and growth and behaviour of cancer cells are likely to be mediated by its ability to regulate the expression of multiple target genes that drive specific cellular effects.…”

Section: Discussionmentioning

confidence: 67%

POU4F2/Brn-3b transcription factor is associated with survival and drug resistance in human ovarian cancer cells

2018

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The development of drug resistance following treatment with chemotherapeutic agents such as cisplatin (cis) and paclitaxel (pax) contributes to high morbidity and mortality in ovarian cancers. However, the molecular mechanisms underlying such changes are not well understood. In this study, we demonstrate that the Brn-3b transcription factor was increased in different ovarian cancer cells including SKOV3 and A2780 following treatment with cis and pax. Furthermore, sustained increases in Brn-3b were associated with survival in drug resistant cells and correlated with elevated HSP27 expression. In contrast, targeting Brn-3b for reduction using short interfering RNA (siRNA) also resulted in attenuated HSP27 expression. Importantly, blocking Brn-3b expression with siRNA in SKOV3 cells was associated with reduced cell numbers at baseline but also increased cell death after further treatment, indicating sensitization of cells. Similar results were obtained in the metastatic IP1 cell line derived from ascites of mice bearing SKOV3 tumours. These findings suggest that increased Brn-3b may confer resistance to chemotherapeutic drugs in ovarian cancer cells by regulating key target genes such as HSP27 and that targeting Brn-3b may provide a novel mechanism for treatment of drug resistant ovarian cancers.

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Section: Discussionmentioning

confidence: 67%

POU4F2/Brn-3b transcription factor is associated with survival and drug resistance in human ovarian cancer cells

2018

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“…AngII-mediated hypertrophic responses in the heart can be elicited by activation of different signalling pathways including p42/44MAPK/ERK, which was shown to activate the Brn-3b promoter in cancer cells 47 . Therefore, we next tested if this pathway also activated the Brn-3b promoter in response to AngII treatment.…”

Section: Resultsmentioning

confidence: 99%

“…This technique was carried out as described by Lee et al and Ounzain et al 38,47 using rat heart-derived H9C2 cells treated with 10 µg/ml AngII for 24 h or untreated for control. Anti-NFAT Ab (BioLegend) was used to immuneprecipitate NFAT proteins bound to the Brn-3b promoter, whereas anti-β-tubulin or 2nd Ab (Dako) was used for negative control ChIP samples.…”

Section: Methodsmentioning

confidence: 99%

The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

Mele¹,

Maskell²,

Stuckey

et al. 2019

Cell Death Dis

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Adult hearts respond to increased workload such as prolonged stress or injury, by undergoing hypertrophic growth. During this process, the early adaptive responses are important for maintaining cardiac output whereas at later stages, pathological responses such as cardiomyocyte apoptosis and fibrosis cause adverse remodelling, that can progress to heart failure. Yet the factors that control transition from adaptive responses to pathological remodelling in the heart are not well understood. Here we describe the POU4F2/Brn-3b transcription factor (TF) as a novel regulator of adaptive hypertrophic responses in adult hearts since Brn-3b mRNA and protein are increased in angiotensin-II (AngII) treated mouse hearts with concomitant hypertrophic changes [increased heart weight:body weight (HW:BW) ratio]. These effects occur specifically in cardiomyocytes because Brn-3b expression is increased in AngII-treated primary cultures of neonatal rat ventricular myocytes (NRVM) or foetal heart-derived H9c2 cells, which undergo characteristic sarcomeric re-organisation seen in hypertrophic myocytes and express hypertrophic markers, ANP/βMHC. The Brn-3b promoter is activated by known hypertrophic signalling pathways e.g. p42/p44 mitogen-activated protein kinase (MAPK/ERK1/2) or calcineurin (via NFAT). Brn-3b target genes, e.g. cyclin D1, GLUT4 and Bax, are increased at different stages following AngII treatment, supporting distinct roles in cardiac responses to stress. Furthermore, hearts from male Brn-3b KO mutant mice display contractile dysfunction at baseline but also attenuated hypertrophic responses to AngII treatment. Hearts from AngII-treated male Brn-3b KO mice develop further contractile dysfunction linked to extensive fibrosis/remodelling. Moreover, known Brn-3b target genes, e.g. GLUT4, are reduced in AngII-treated Brn-3b KO hearts, suggesting that Brn-3b and its target genes are important in driving adaptive hypertrophic responses in stressed heart.

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“…POU4F2 is overexpressed in breast cancer and neuroblastoma cells, in which it promotes tumor growth [34,35]. In breast cancer, POU4F2 can repress BRCA1 expression [36] and interact with estrogen receptor alpha to enhance its activity [35].…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, POU4F2 can repress BRCA1 expression [36] and interact with estrogen receptor alpha to enhance its activity [35]. POU4F2 can also induce the expression of CCD1 and CDK4 in the context of proliferation and cell cycle progression [34,37], confer migratory and multidrug resistance properties to breast cancer in in vivo models [38], and cooperate with TP53 to increase transcription of pro-apoptotic genes [39].…”

Section: Discussionmentioning

confidence: 99%

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

et al. 2016

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BackgroundLung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.Methods and FindingsWe performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10−50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. Our study’s limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.ConclusionsThese data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.

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Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERα and growth factors via MAPK pathway

Cited by 13 publications

References 27 publications

POU4F2/Brn-3b transcription factor is associated with survival and drug resistance in human ovarian cancer cells

POU4F2/Brn-3b transcription factor is associated with survival and drug resistance in human ovarian cancer cells

The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

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