Disruption of super-enhancer-driven tumor suppressor gene RCAN1.4 expression promotes the malignancy of breast carcinoma

Deng, Rong; Huang, Junhao; Wang, Yan; Zhou, Lei; Wang, Zi-Feng; Hu, Bingxin; Chen, Yuhong; Yang, Dong; Mai, Jia; Li, Zhiling; Zhang, Hai-Liang; Huang, Yun; Peng, Xiaoxue; Gao, Feng; Zhu, Xiao‐Feng; Tang, Jun

doi:10.1186/s12943-020-01236-z

Cited by 49 publications

(24 citation statements)

References 47 publications

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“…SEs are occupied by various transcription factors, cofactors, and histone modifications ( Whyte et al, 2013 ; Khan and Zhang, 2019 ; Deng et al, 2020 ). Compared with TEs, SEs can not only promote gene transcription more efficiently ( Bae et al, 2016 ) but also regulate cell-type-specific gene regulatory networks ( Hnisz et al, 2013 ), define cell identity and contribute to the development of diseases ( Niederriter et al, 2015 ; Kang et al, 2020 ) such as neuroblastoma ( van Groningen et al, 2017 ) and cancer.…”

Section: Discussionmentioning

confidence: 99%

Super Enhancer Profiles Identify Key Cell Identity Genes During Differentiation From Embryonic Stem Cells to Trophoblast Stem Cells Super Enhencers in Trophoblast Differentiation

et al. 2021

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Trophoblast stem cells (TSCs) are derived from blastocysts and the extra-embryonic ectoderm (ExE) of post-implantation embryos and play a significant role in fetal development, but the roles that TSCs play in the earlier status of fetal diseases need further exploration. Super enhancers (SEs) are dense clusters of stitched enhancers that control cell identity determination and disease development and may participate in TSC differentiation. We identified key cell identity genes regulated by TSC-SEs via integrated analysis of H3K27ac and H3K4me1 chromatin immunoprecipitation sequencing (ChIP-seq), RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) data. The identified key TSC identity genes regulated by SEs, such as epidermal growth factor receptor (EGFR), integrin β5 (ITGB5) and Paxillin (Pxn), were significantly upregulated during TSC differentiation, and the transcription network mediated by TSC-SEs enriched in terms like focal adhesion and actin cytoskeleton regulation related to differentiation of TSCs. Additionally, the increased chromatin accessibility of the key cell identity genes verified by ATAC-seq further demonstrated the regulatory effect of TSC-SEs on TSC lineage commitment. Our results illustrated the significant roles of the TSC-SE-regulated network in TSC differentiation, and identified key TSC identity genes EGFR, ITGB5 and Pxn, providing novel insight into TSC differentiation and lays the foundation for future studies on embryo implantation and related diseases.

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Section: Discussionmentioning

confidence: 99%

Super Enhancer Profiles Identify Key Cell Identity Genes During Differentiation From Embryonic Stem Cells to Trophoblast Stem Cells Super Enhencers in Trophoblast Differentiation

et al. 2021

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“…Therefore, the identification of key TFs is of great significance to the research of super-enhancers. According to the method of Deng et al 38 to identify TFs, we analyzed E1 component enhancer region and EphA2 core promoter region that bind to TFs and enriched with H3K27ac, H3K4me1 and H3K4me3 from ChIP-seq of ENCODE project. Among the 340 TFs of ENCODE project, we found that 115 TFs bind to the E1 component enhancer region, which overlaps with the region characterized by the enrichment of H3K27ac and H3K4me1 markers (Fig.…”

Section: Resultsmentioning

confidence: 99%

EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2

Cui

Liu

et al. 2021

Cell Death Dis

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Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.

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“…However, they are deregulated in many human cancers. Along with them, lncRNAs derived from the transcription of active enhancers are differentially expressed in cancer tissues and have been revealed to act as oncogenes, promoting the transcriptional activation of the oncogenic pathways and even inducing chromosomal rearrangements and genomic instability [ 115 , 116 , 117 , 118 ].…”

Section: Transcriptional Gene Modulation By Lncrnasmentioning

confidence: 99%

Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

García-Padilla

Dueñas

García‐López

et al. 2022

IJMS

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Deep whole genome and transcriptome sequencing have highlighted the importance of an emerging class of non-coding RNA longer than 200 nucleotides (i.e., long non-coding RNAs (lncRNAs)) that are involved in multiple cellular processes such as cell differentiation, embryonic development, and tissue homeostasis. Cancer is a prime example derived from a loss of homeostasis, primarily caused by genetic alterations both in the genomic and epigenetic landscape, which results in deregulation of the gene networks. Deregulation of the expression of many lncRNAs in samples, tissues or patients has been pointed out as a molecular regulator in carcinogenesis, with them acting as oncogenes or tumor suppressor genes. Herein, we summarize the distinct molecular regulatory mechanisms described in literature in which lncRNAs modulate carcinogenesis, emphasizing epigenetic and genetic alterations in particular. Furthermore, we also reviewed the current strategies used to block lncRNA oncogenic functions and their usefulness as potential therapeutic targets in several carcinomas.

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Disruption of super-enhancer-driven tumor suppressor gene RCAN1.4 expression promotes the malignancy of breast carcinoma

Cited by 49 publications

References 47 publications

Super Enhancer Profiles Identify Key Cell Identity Genes During Differentiation From Embryonic Stem Cells to Trophoblast Stem Cells Super Enhencers in Trophoblast Differentiation

Super Enhancer Profiles Identify Key Cell Identity Genes During Differentiation From Embryonic Stem Cells to Trophoblast Stem Cells Super Enhencers in Trophoblast Differentiation

EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2

Molecular Mechanisms of lncRNAs in the Dependent Regulation of Cancer and Their Potential Therapeutic Use

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