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Transcriptional reprogramming by AP-1-bound cis-regulatory elements drives melanoma development

ABSTRACT: Malignant melanoma is characterized by high metastatic potential and cellular plasticity. Its progression is driven not only by genetic alterations but also by epigenetic repro-gramming and changes in the transcriptome, mediated by transcription factors. The AP-1 family favors an invasive cell state by facilitating processes such as angiogenesis and migration. However, the AP-1-driven regulatory landscape and its implications for melanoma plasticity remain poorly understood. Here, we further elucidate the role of the AP-1 members c-Jun and Fra-1 in enhancer-driven gene regulation during melanoma development. Integrative ChIP-seq and RNA-seq analyses revealed extensive enhancer reprogramming during tumor formation and significant upregulation of genes annotated to enhancers gained in melanoma cells. On average, half of these regions are directly bound by c-Jun/Fra-1, given a high AP-1 motif rate (~80%) and chromatin accessibility. Enhancer-regulated c-Jun/Fra-1 targets are functionally linked to an invasive phenotype and comprise well-known melanoma drivers involved in migration and EMT. Clinically, high c-Jun/Fra-1 and target gene expression correlate with poor survival in BRAF wild-type and NRAS mutant melanoma patients, highlighting c-Jun/Fra-1 as a potential biomarker and therapeutic target. Overall, our data identify c-Jun/Fra-1 as major drivers of melanoma development through enhancer-mediated transcriptional programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326324 | GEO | 2026/07/21

REPOSITORIES: GEO

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Liver cancer development driven by the AP-1/c-Jun~Fra2 dimer through c-Myc

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Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (expression)

Project description:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity. BT549 cells grown in complete medium were transfected with a control siRNA, siRNA targeting Fra-1 or siRNA targeting c-Jun for 72 h, and then global gene expression profiles were assessed. Three or four biological replicates were used for each group.

2014-06-30 | E-GEOD-46440 | biostudies-arrayexpress

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (expression)

2014-06-30 | GSE46440 | GEO

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (ChIP-seq)

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Dissecting AP-1 complexity in hepatic health and disease using Genetically Modified Mice

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Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression

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Expression profiling of lung tissue from 6-, 10- and 14-week-old Fra2 transgenic male mice

Project description:The transcription factor complex AP-1 (Activator protein 1) is composed of Jun (c-Jun, JunB, JunD) and Fos proteins (c-Fos, FosB, Fra-1, Fra-2) which control a variety of stress responses, including cell proliferation, apoptosis, inflammation, wound healing, and cancer. Individual Fos proteins have been thoroughly studied in gain- and loss-of-function mouse models, which revealed important functions in bone cell proliferation and differentiation. We have recently demonstrated that loss of Fra-2 causes perinatal lethality and severe osteopenia due to several cellular defects, including a chondrocyte differentiation defect and a control of osteoclast survival and size. Moreover, we have reported a profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestations in the lung. Fra-2 knock-out newborns have increased numbers and size of osteoclasts in vivo. The pulmonary phenotype observed in Fra-2Tg mice is characterized by vascular remodeling and obliteration of pulmonary arteries, which coincides with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations are followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5.

2011-12-01 | GSE23745 | GEO

Expression profiling of lung tissue from 6-, 10- and 14-week-old Fra2 transgenic male mice

2011-12-01 | E-GEOD-23745 | biostudies-arrayexpress

AP-1 family members act at DNA targets in conjunction with Sox9 to promote chondrocyte hypertrophy

Project description:A comprehensive analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif (Ohba et al. 2015). Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, a reflection of direct binding of each factor to target motifs in shared enhancers, and physical interactions of AP-1 with Sox9. In vitro expression analysis indicates that direct co-binding of Sox9 and AP-1 at target motifs enhanced target gene expression, while protein-protein interactions suppressed AP-1- and Sox9-driven transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 demonstrated Sox9 was essential for hypertrophic chondrocyte development, while in vitro and ex vivo analyses showed AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model where AP-1-family members promote Sox9-action in the transition of chondrocytes to a terminal hypertrophic program. Intersection of ChIP-seq data from Sox9 and AP-1 factor Jun, RNA-seq data from developing rib chondrocytes and Col10a1mCherry positive hypertrophic chondrocytes in neonatal mice to uncover regulation of Sox9 by AP-1 factors during chondrocyte hypertrophy.

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HDAC8 regulates escape from BRAF inhibitor therapy in Melanoma: Phosphotyrosine Profiling

Project description:Melanoma cells are highly plastic and have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanoma cell lines and patient specimens to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia and UV-irradiation leads to an increase in histone deacetylase 8 (HDAC8) expression/activity, and in turn, the adoption of a drug-resistant, invasive phenotype. Systems level analyses using mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling pathways. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both in vitro and in in vivo xenograft models. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase (RTK) activation leading to Ras/CRAF/MEK/ERK signaling. Although HDACs primarily function at the histone level, they also regulate signaling through the modulation of non-histone substrates. In line with this, HDAC8 introduction decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine residue 273 reduced the transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition through increased RTK expression and enhanced MAPK pathway activity. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both non-selective and HDAC8-specific inhibitors enhancing the durability of response to BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors could represent an excellent strategy to limit the adaptation of melanoma cells to multiple stresses and therapeutic interventions, including BRAF-MEK inhibitor combinations.

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