Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma

Xie, Jian Jun; Jiang, Yan; Jiang, Yuan; Li, Chun Quan; Lim, Mei Chee; An, Ömer; Mayakonda, Anand; Ding, Ling-Wen; Lin, Li-Wen; Sun, Changgang; Lin, Le Hang; Chen, Li; Wu, Jian; Wu, Zhi Yong; Cao, Qi; Fang, Wang‐Kai; Yang, Wei; Soukiasian, Harmik J.; Meltzer, Stephen J.; Yang, Henry; Fullwood, Melissa J.; Li, Xu; Li, En Min; Lin, De; Koeffler, H. Phillip

doi:10.1053/j.gastro.2018.02.018

Cited by 175 publications

(138 citation statements)

References 53 publications

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“…SE-assigned genes were annotated, including well-known SCC oncogenes-TP63, SOX2, KLF5, CCAT1, CTTN, EGFR Jiang et al, 2017;Watanabe et al, 2014;Xie et al, 2018) ( Figure S1A; Tables S1, S2 and S3). We next performed assay of transposase-accessible chromatin with sequencing (ATAC-seq), which showed high concordance with H3K4me1 and H3K27ac signals, as ATAC-seq signals were located at valley regions of H3K4me1 and H3K27ac peaks ( Figure 1A),…”

Section: Identification and Characterization Of Crc Program In Esccmentioning

confidence: 99%

“…The functional requirements of TP63 and SOX2 for ESCC have been established Jiang et al, 2017;Xie et al, 2018). However, the biological significance of KLF5 in ESCC is comparably less investigated.…”

Section: Identification and Characterization Of Crc Program In Esccmentioning

confidence: 99%

“…These epigenetic characteristics are also notably altered in disease states, such as cancer. In particular, we and others have shown that the clusters of active enhancers called super-enhancers (SEs) mediate transcriptional dysregulation in human cancers (Chipumuro et al, 2014;Hnisz et al, 2013;Jiang et al, 2017;Xie et al, 2018;Yuan et al, 2017). These SE loci are occupied by high density of lineage-or cell type-specific transcription factors (TFs), chromatin regulators and coactivators to govern gene expression networks and hence contribute profoundly to cancer biology Hnisz et al, 2017;Whyte et al, 2013).…”

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confidence: 99%

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TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

Jiang

et al. 2019

Preprint

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novel CRC target contributing to ESCC viability. Using circular chromosome conformation capture sequencing (4C-seq) and CRISPR/Cas9 genome editing, the direct interaction between TP63 promoter and functional enhancers which is mediated by CRC TFs is identified. Deletion of each enhancer decreases expression of CRC TFs and impairs cell viability, phenocopying the knockdown of each CRC TF.Targeting epigenetic regulation by inhibition of either the BET bromodomain or HDAC disrupts the CRC program and its dependent global epigenetic modification, consequently suppressing ESCC tumor growth. Importantly, combination of both compounds result in synergistic anti-tumor effect.

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Section: Identification and Characterization Of Crc Program In Esccmentioning

confidence: 99%

Section: Identification and Characterization Of Crc Program In Esccmentioning

confidence: 99%

mentioning

confidence: 99%

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TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

Jiang

et al. 2019

Preprint

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“…For example, LINC00336 was reported to facilitate lung cancer progression via sponging miR‐6,852; LncRNA SNHG6 directly bound to miR‐26a/b and miR‐214 to promote the growth and metastasis of colorectal cancer; LncRNA MEG3 was proposed to suppress migration and promote apoptosis of oral squamous cell carcinoma cells by effectively sponging miR‐548d‐3p . Likewise, several lncRNAs have also been identified to be involved in ESCC tumorigenesis, such as HOTTIP, EGFR‐AS1, FAL1, and LINC01503 . Thus, although a small fraction of lncRNAs in cancer have been well delineated, the roles of many members in this class are still unknown, which needs to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…11 Likewise, several lncRNAs have also been identified to be involved in ESCC tumorigenesis, such as HOTTIP, 12 EGFR-AS1, 13 FAL1, 14 and LINC01503. 15 Thus, although a small fraction of lncRNAs in cancer have been well delineated, the roles of many members in this class are still unknown, which needs to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

p53‐induced long non‐coding RNA PGM5‐AS1 inhibits the progression of esophageal squamous cell carcinoma through regulating miR‐466/PTEN axis

et al. 2019

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A growing body of evidence suggests that long non‐coding RNA (lncRNA) is aberrantly expressed in human cancer and linked to cancer initiation and development. We previously identified Homo sapiens PGM5 antisense RNA 1 (PGM5‐AS1) as a novel esophageal squamous cell carcinoma (ESCC)‐related lncRNA by performing high‐throughput RNA sequencing. However, its clinical implication and biological function in ESCC are still uncharacterized. In the present study, we found that PGM5‐AS1 was frequently downregulated in ESCC tissues, plasma, and cell lines, and low PGM5‐AS1 expression was positively correlated with poor differentiation, advanced tumor node metastasis (TNM) stage, and lymph node metastasis. Importantly, PGM5‐AS1 was identified to be an effective diagnostic and prognostic biomarker for ESCC patients. Functional experiments revealed that exogenous expression of PGM5‐AS1 significantly suppressed the proliferation, migration, and invasion of ESCC cells in vitro as well as tumor growth in vivo. Mechanistically, PGM5‐AS1 was transcriptionally activated by p53 and it could directly interact with and sequester miR‐466 to elevate PTEN expression, thereby inhibiting ESCC progression. Overall, our data indicate that PGM5‐AS1 is a novel tumor suppressor in ESCC and restoration of PGM5‐AS1 may be a promising avenue for treatment of ESCC patient.

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Characterization of super‐enhancer‐associated functional lncRNAs acting as ceRNAs in ESCC

et al. 2020

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Long noncoding RNAs (lncRNAs) have important regulatory roles in cancer biology. Although some lncRNAs have well‐characterized functions, the vast majority of this class of molecules remains functionally uncharacterized. To systematically pinpoint functional lncRNAs, a computational approach was proposed for identification of lncRNA‐mediated competing endogenous RNAs (ceRNAs) through combining global and local regulatory direction consistency of expression. Using esophageal squamous cell carcinoma (ESCC) as model, we further identified many known and novel functional lncRNAs acting as ceRNAs (ce‐lncRNAs). We found that most of them significantly regulated the expression of cancer‐related hallmark genes. These ce‐lncRNAs were significantly regulated by enhancers, especially super‐enhancers (SEs). Landscape analyses for lncRNAs further identified SE‐associated functional ce‐lncRNAs in ESCC, such as HOTAIR, XIST, SNHG5, and LINC00094. THZ1, a specific CDK7 inhibitor, can result in global transcriptional downregulation of SE‐associated ce‐lncRNAs. We further demonstrate that a SE‐associated ce‐lncRNA, LINC00094 can be activated by transcription factors TCF3 and KLF5 through binding to SE regions and promoted ESCC cancer cell growth. THZ1 downregulated expression of LINC00094 through inhibiting TCF3 and KLF5. Our data demonstrated the important roles of SE‐associated ce‐lncRNAs in ESCC oncogenesis and might serve as targets for ESCC diagnosis and therapy.

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Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma

Abstract: We identified an lncRNA, LINC01503, which is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients.

Cited by 175 publications

References 53 publications

TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

p53‐induced long non‐coding RNA PGM5‐AS1 inhibits the progression of esophageal squamous cell carcinoma through regulating miR‐466/PTEN axis

Characterization of super‐enhancer‐associated functional lncRNAs acting as ceRNAs in ESCC

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