The hyper-activation of transcriptional enhancers in breast cancer

Li, Qinglan; Wang, Danya; Ju, Lingao; Yao, Jie; Gao, Chuan; Lei, Pin‐Ji; Li, Lianyun; Zhao, Xiaolu; Wu, Min

doi:10.1186/s13148-019-0645-x

Cited by 47 publications

(48 citation statements)

References 34 publications

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“…Our data on SEs bound by the AR expand on the role of SEs recently shown for other cancer types, in some cases allowing for stratification predictive of treatment response (Cejas et al, 2019;Gelato et al, 2018;Zhang et al, 2016). Interestingly, in breast cancer, estrogen receptor-bound SEs are also bound by MED1 and FOXA1, which act as facilitators for the interaction with neighboring enhancers (Bojcsuk et al, 2017), and lists of highly active SEs which potentially play a critical role in this tumor type have just been reported (Hazan et al, 2019;Li et al, 2019). Another important recent finding is that oncogenic SEs are inclined to undergo double-strand breaks and are therefore highly vulnerable to deficiencies in cellular DNA repair mechanisms.…”

Section: Resultssupporting

confidence: 76%

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

et al. 2020

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Prostate cancer (PCa) is one of the most frequent tumor types in the male Western population. Early-stage PCa and late-stage PCa are dependent on androgen signaling, and inhibitors of the androgen receptor (AR) axis represent the standard therapy. Here, we studied in detail the global impact of darolutamide, a newly approved AR antagonist, on the transcriptome and AR-bound cistrome in two PCa cell models. Darolutamide strongly depleted the AR from gene regulatory regions and abolished AR-driven transcriptional signaling. Enhancer activation was blocked at the chromatin level as evaluated by H3K27 acetylation (H3K27ac), H3K4 monomethylation (H3K4me1), and FOXA1, MED1, and BRD4 binding. We identified genomic regions with high affinities for the AR in androgen-stimulated, but also in androgen-depleted conditions. A similar AR affinity pattern was observed in healthy and PCa tissue samples. High FOXA1, BRD4, H3K27ac, and H3K4me1 levels were found to mark regions showing AR binding in the hormone-depleted setting. Conversely, low FOXA1, BRD4, and H3K27ac levels were observed at regulatory sites that responded strongly to androgen stimulation, and AR interactions at these sites were blocked by darolutamide. Beside marked loss of AR occupancy, FOXA1 recruitment to chromatin was also clearly reduced after darolutamide treatment. We furthermore identified numerous androgen-regulated super-enhancers (SEs) that were associated with hallmark androgen and cell proliferation-associated gene sets. Importantly, these SEs are also active in PCa tissues and sensitive to darolutamide treatment in our models. Our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR enhancer and SE activation, and downstream transcription. We also show the existence of a dynamic AR cistrome that depends on the androgen levels and on high AR affinity regions present in PCa cell lines and also in tissue samples.

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Section: Resultssupporting

confidence: 76%

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

et al. 2020

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“…Lower levels of H4K5 and H4K8 acetylation are seen in 4C, 4C11−, and 4C11+ in comparison to melan-a cells. In parallel, the H4K12ac and H4K16ac changed across the multiple pairwise comparisons correlated with poor patient outcomes [68] and the decrease in H3K23me1 was also verified in breast cancer when compared to normal tissues [69].…”

Section: Discussionmentioning

confidence: 86%

“…H3K9me2 levels were also found to be increased in melanoma compared to normal skin tissue [ 66 ] whereas H3K27me3 levels were lower in metastatic versus primary melanoma cases [ 67 ]. In parallel, low H3K18ac levels in cancer were already correlated with poor patient outcomes [ 68 ] and the decrease in H3K23me1 was also verified in breast cancer when compared to normal tissues [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

et al. 2020

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Background: We have previously developed a murine cellular system that models the transformation from melanocytes to metastatic melanoma cells. This model was established by cycles of anchorage impediment of melanocytes and consists of four cell lines: differentiated melanocytes (melan-a), pre-malignant melanocytes (4C), malignant (4C11−), and metastasis-prone (4C11+) melanoma cells. Here, we searched for transcriptional and epigenetic signatures associated with melanoma progression and metastasis by performing a gene co-expression analysis of transcriptome data and a mass-spectrometry-based profiling of histone modifications in this model. Results: Eighteen modules of co-expressed genes were identified, and some of them were associated with melanoma progression, epithelial-to-mesenchymal transition (EMT), and metastasis. The genes in these modules participate in biological processes like focal adhesion, cell migration, extracellular matrix organization, endocytosis, cell cycle, DNA repair, protein ubiquitination, and autophagy. Modules and hub signatures related to EMT and metastasis (turquoise, green yellow, and yellow) were significantly enriched in genes associated to patient survival in two independent melanoma cohorts (TCGA and Leeds), suggesting they could be sources of novel prognostic biomarkers. Clusters of histone modifications were also linked to melanoma progression, EMT, and metastasis. Reduced levels of H4K5ac and H4K8ac marks were seen in the pre-malignant and tumorigenic cell lines, whereas the methylation patterns of H3K4, H3K56, and H4K20 were related to EMT. Moreover, the metastatic 4C11+ cell line showed higher H3K9me2 and H3K36me3 methylation, lower H3K18me1, H3K23me1, H3K79me2, and H3K36me2 marks and, in agreement, downregulation of the H3K36me2 methyltransferase Nsd1.

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“…We speculated that about 31% (201/645) of tumor-altered H3K4me3 regions, which do not overlap with TSSs (‘altered.noTSS’ promoters), may represent a subclass of enhancers in tumor samples. GeneHancer was recently introduced as a comprehensive database of human enhancers and their inferred target genes [ 47 ]. GeneHancer revealed that 152/201 (>75%) of ‘altered.noTSS’ promoters intersected with enhancers and then predicted the corresponding targeted genes ( Table S12 ).…”

Section: Resultsmentioning

confidence: 99%

Integrative RNA-Seq and H3 Trimethylation ChIP-Seq Analysis of Human Lung Cancer Cells Isolated by Laser-Microdissection

Ong

Sakashita

Hanawa

et al. 2021

Cancers

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Our previous integrative study in gastric cancer discovered cryptic promoter activation events that drive the expression of important developmental genes. However, it was unclear if such cancer-associated epigenetic changes occurred in cancer cells or other cell types in bulk tissue samples. An integrative analysis consisting of RNA-Seq and H3K4me3 ChIP-Seq was used. This workflow was applied to a set of matched normal lung tissues and non-small cell lung cancer (NSCLC) tissues, for which the stroma and tumor cell parts could be isolated by laser-microdissection microscopy (LMD). RNA-Seq analysis showed subtype-specific differential expressed genes and enriched pathways in NSCLC. ChIP-Seq analysis results suggested that the proximal altered H3K4me3 regions were located at differentially expressed genes involved in cancer-related pathways, while altered distal H3K4me3 regions were annotated with enhancer activity of cancer regulatory genes. Interestingly, integration with ENCODE data revealed that proximal tumor-gained promoters were associated with EZH2 and SUZ12 occupancies, which are the core components of polycomb repressive complex 2 (PRC2). This study used LMD on clinical samples for an integrative analysis to overcome the tissue heterogeneity problem in cancer research. The results also contribute to the overall understanding of genetic and epigenetic dysregulation of lung malignancy.

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The hyper-activation of transcriptional enhancers in breast cancer

Cited by 47 publications

References 34 publications

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

Integrative RNA-Seq and H3 Trimethylation ChIP-Seq Analysis of Human Lung Cancer Cells Isolated by Laser-Microdissection

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