Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis

Ye, Bo; Fan, Dandan; Xiong, Wei; Li, Min; Yuan, Jian; Jiang, Qi; Zhao, Yuting; Lin, Jianxiang; Liu, Jie; Lv, Yilv; Wang, Xiongjun; Li, Zhigang; Su, Jianzhong; Qiao, Yong

doi:10.1038/s41467-021-24813-2

Cited by 37 publications

(22 citation statements)

References 77 publications

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“…At the mechanistic level, SEs inhibition hinders the transcription of stemness and pro-metastatic genes [ 94 ]. Another advanced study identified a plethora of SEs assembled in esophageal squamous cell carcinoma (ESCC) and metastatic lymph node cancer (LNC) cells [ 95 ]. Based on H3K27ac profiling, SEs signatures were precisely defined in primary and lymph node tumors.…”

Section: Dna Grammar and Syntax Features And Epigenetic Characteristi...mentioning

confidence: 99%

Typical Enhancers, Super-Enhancers, and Cancers

Koutsi

Pouliou

Champezou

et al. 2022

Cancers

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Non-coding segments of the human genome are enriched in cis-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the “archetype” gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity, and the epigenomic features of the chromatin microenvironment across which these regulatory elements reside. Here, we comprehensively describe: fundamental mechanisms of gene expression dysregulation in cancers that involve genomic abnormalities within enhancers’ and Super-enhancers’ (SEs) sequences, which alter the expression of oncogenic transcription factors (TFs); cutting-edge technologies applied for the analysis of variation-enriched hotspots of the cancer genome; and pharmacological approaches for the treatment of Super-enhancers’ aberrant function. Finally, we provide an intratumor meta-analysis, which highlights that genomic variations in transcription-factor-driven tumors are accompanied overexpression of genes, a portion of which encodes for additional cancer-related transcription factors.

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Section: Dna Grammar and Syntax Features And Epigenetic Characteristi...mentioning

confidence: 99%

Typical Enhancers, Super-Enhancers, and Cancers

Koutsi

Pouliou

Champezou

et al. 2022

Cancers

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“…There are two major subtypes of Esophageal cancer (EC), esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) ( Ye et al, 2021 ). In China, more than 90% of esophageal cancer cases are ESCC ( Zhang X. et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Drug repositioning for esophageal squamous cell carcinoma

Bennett

Huang

et al. 2022

Front. Genet.

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Esophageal cancer (EC) remains a significant challenge globally, having the 8th highest incidence and 6th highest mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common form of EC in Asia. Crucially, more than 90% of EC cases in China are ESCC. The high mortality rate of EC is likely due to the limited number of effective therapeutic options. To increase patient survival, novel therapeutic strategies for EC patients must be devised. Unfortunately, the development of novel drugs also presents its own significant challenges as most novel drugs do not make it to market due to lack of efficacy or safety concerns. A more time and cost-effective strategy is to identify existing drugs, that have already been approved for treatment of other diseases, which can be repurposed to treat EC patients, with drug repositioning. This can be achieved by comparing the gene expression profiles of disease-states with the effect on gene-expression by a given drug. In our analysis, we used previously published microarray data and identified 167 differentially expressed genes (DEGs). Using weighted key driver analysis, 39 key driver genes were then identified. These driver genes were then used in Overlap Analysis and Network Analysis in Pharmomics. By extracting drugs common to both analyses, 24 drugs are predicted to demonstrate therapeutic effect in EC patients. Several of which have already been shown to demonstrate a therapeutic effect in EC, most notably Doxorubicin, which is commonly used to treat EC patients, and Ixazomib, which was recently shown to induce apoptosis and supress growth of EC cell lines. Additionally, our analysis predicts multiple psychiatric drugs, including Venlafaxine, as repositioned drugs. This is in line with recent research which suggests that psychiatric drugs should be investigated for use in gastrointestinal cancers such as EC. Our study shows that a drug repositioning approach is a feasible strategy for identifying novel ESCC therapies and can also improve the understanding of the mechanisms underlying the drug targets.

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“…SEs can be acquired by cancer cells at key oncogenes, 9,11 and over 60% of SEs are tissue‐ or cancer‐type‐specific 9,12 . Furthermore, recent studies have indicated the significance of SEs‐associated genes as potential therapeutic targets for several cancers 13,14 . Although increasing evidence suggested that SEs play critical roles in the development of a broad range of cancers, 12,15–17 the functional characterization and clinical significance of SEs in LUAD have not been comprehensively investigated.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization and clinical significance of super‐enhancers in lung adenocarcinoma

Jiang

Qin

Hua

et al. 2022

Molecular Carcinogenesis

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Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration)and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy.

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Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis

Cited by 37 publications

References 77 publications

Typical Enhancers, Super-Enhancers, and Cancers

Typical Enhancers, Super-Enhancers, and Cancers

Drug repositioning for esophageal squamous cell carcinoma

Functional characterization and clinical significance of super‐enhancers in lung adenocarcinoma

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