Hepatocyte nuclear factor HNF1A is a potential regulator in shaping the super‐enhancer landscape in colorectal cancer liver metastasis

Cai, Chunmiao; Bi, Dexi; Bick, Gregory; Wei, Qing; Liu, Hu; Lu, Ling; Zhang, Xiaoting; Qin, Huanlong

doi:10.1002/1873-3468.14219

Cited by 6 publications

(4 citation statements)

References 59 publications

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“… SEs regulation of these genes was confirmed using CRISPR — Unknown, probably, overexpression of CDK12, elongation regulator and crucial component of SE machinery. SEs formation Metastasis, cell proliferation, migration, invasion, survival, stemness SR-4835, selective inhibitor of CDK12 [ 153 ] CRC (liver metastasis) — Primary samples, KM12SM, V410, V457, V576, V784, V855, V866 64% of primary samples Integrins, S100A family, cadherins, filamins, collagens, HAS, laminins, TGF-beta family, Wnt family, targets of Wnt pathway — HNF-1α (a key regulator), AP1, ETS, FOX, and KLF families HNF1-alpha upregulates transcription-changing SE landscapes and must be a key regulator in liver metastasis Wnt pathway, TGF-beta pathway, EMT — [ 335 ] Gastric (stomach) adenocarcinoma (STAD) — 11 primary samples, AGS, MKN45 cells — TM4SF1-AS1 (representative lncRNA) SE-associated lncRNA TM4SF1-AS1 suppresses T-cell-mediated immune killing — — Immunosurveillance, cancer microRNAs, cellular senescence, protein folding in endoplasmic reticulum, cell cycle — [ 188 ] STAD EBV, CIN (chromosomal instability), GS (genomically stable) STAD subtypes Based on histology: 10 gland-forming adenocarcinomas (53%, intestinal type), 6 samples with highly infiltrating isolated cells (32%, diffuse type) 3 GC samples (15%) of mixed histology OCUM-1, SNU16, FU97, KATOIII, MKN7, NCC-59, RERF-GC-1B, YCC-21, YCC-22, YCC-3, YCC-7 cells, 19 primary (1 EBV, 10 GS, 8 GIN) samples …”

Section: Table A1mentioning

confidence: 99%

Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status

Vasileva,

Gladkova,

Ashniev

et al. 2024

IJMS

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Super-enhancers (SEs) are regions of the genome that play a crucial regulatory role in gene expression by promoting large-scale transcriptional responses in various cell types and tissues. Recent research suggests that alterations in super-enhancer activity can contribute to the development and progression of various disorders. The aim of this research is to explore the multifaceted roles of super-enhancers in gene regulation and their significant implications for understanding and treating complex diseases. Here, we study and summarise the classification of super-enhancer constituents, their possible modes of interaction, and cross-regulation, including super-enhancer RNAs (seRNAs). We try to investigate the opportunity of SE dynamics prediction based on the hierarchy of enhancer single elements (enhancers) and their aggregated action. To further our understanding, we conducted an in silico experiment to compare and differentiate between super-enhancers and locus-control regions (LCRs), shedding light on the enigmatic relationship between LCRs and SEs within the human genome. Particular attention is paid to the classification of specific mechanisms and their diversity, exemplified by various oncological, cardiovascular, and immunological diseases, as well as an overview of several anti-SE therapies. Overall, the work presents a comprehensive analysis of super-enhancers across different diseases, aiming to provide insights into their regulatory roles and may act as a rationale for future clinical interventions targeting these regulatory elements.

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Section: Table A1mentioning

confidence: 99%

Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status

Vasileva,

Gladkova,

Ashniev

et al. 2024

IJMS

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“…Liver-specific TFs such as FOXA2 and HNF1A bind to altered TEs and SEs in the CRC cells and activate liver-specific gene transcription that drives liver metastasis [57]. Furthermore, HNF1A is overexpressed and HNF1Abinding motifs are enriched in the SEs during liver metastasis in CRC [58]. Transcriptional reprogramming mediated by SEs also promotes HCC progression.…”

Section: Se Participate In the Transcription Reprogramming Of Oncogenesmentioning

confidence: 99%

The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors

Li¹,

Qu²,

Teng³

et al. 2023

Int. J. Biol. Sci.

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Digestive system tumors include malignancies of the stomach, pancreas, colon, rectum, and the esophagus, and are associated with high morbidity and mortality. Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. The aberrant transcription of key oncogenes is driven by super-enhancers (SEs), which are characterized by large clusters of enhancers with significantly high density of transcription factors, cofactors, and epigenetic modulatory proteins. The SEs consist of critical epigenetic regulatory elements, which modulate the biological characteristics of digestive system tumors including tumor cell identity and differentiation, tumorigenesis, environmental response, immune response, and chemotherapeutic resistance. The core transcription regulatory loop of the digestive system tumors is complex and a high density of transcription regulatory complexes in the SEs and the crosstalk between SEs and the noncoding RNAs. In this review, we summarized the known characteristics and functions of the SEs in the digestive system tumors. Furthermore, we discuss the oncogenic roles and regulatory mechanisms of SEs in the digestive system tumors. We highlight the role of SE-driven genes, enhancer RNAs (eRNAs), lncRNAs, and miRNAs in the digestive system tumor growth and progression. Finally, we discuss clinical significance of the CRISPR-Cas9 gene editing system and inhibitors of SE-related proteins such as BET and CDK7 as potential cancer therapeutics.

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“…1,2 The hepatic nuclear factor-1A (HNF1A) gene codes for a transcription factor that regulates the expression of genes in the liver, intestine, pancreas, and kidney. 9,10 Transcription of the lncRNA, HNF1A-AS1 (HNF1Aantisense RNA 1), initiates within the first intron of the HNF1A gene. HNF1A-AS1 plays a significant role in a variety of cancers including hepatocellular carcinoma, oral squamous cell carcinoma, 11 gastric cancer, 12 urothelial carcinoma of the bladder, 13 bladder cancer, non-small cell lung cancer, 14,15 colorectal cancer, 16 osteosarcoma, 17 and esophageal adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

“…The hepatic nuclear factor‐1A ( HNF1A ) gene codes for a transcription factor that regulates the expression of genes in the liver, intestine, pancreas, and kidney 9,10 . Transcription of the lncRNA, HNF1A‐AS1 (HNF1A – antisense RNA 1), initiates within the first intron of the HNF1A gene.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of HNF1A and HNF1A‐AS1 in colon cancer cells

et al. 2022

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The human hepatocyte nuclear factor 1 homeobox A (HNF1A) gene loci express the protein‐coding HNF1A transcript and a long non‐coding RNA in the anti‐sense (HNF1A‐AS1) direction. HNF1A‐AS1 is expressed in numerous types of cancers and poor clinical outcomes such as higher mortality rates, greater metastatic capacity, and poor prognosis of the disease are the results of this expression. In this study, we determined the epigenetic features of the HNF1A gene loci, and expression and cellular localization of HNF1A‐AS1 RNA, HNF1A RNA, and HNF1A protein in colorectal cancer (HT‐29, HTC116, RKO, and SW480) and normal colon epithelial (CCD841) cells. The HT‐29 HNF1A gene had active histone marks (H3K4me3, H3K27ac) and DNase 1 accessible sites at the promoter regions of the HNF1A and HNF1A‐AS1 genes. These epigenetic marks were not observed in the other colorectal cancer cells or in the normal colon epithelial cells. Consistent with the active gene epigenetic signature of the HNF1A gene in HT‐29 cells, HNF1A protein, and HNF1A/HNF1A‐AS1 transcripts were detected in HT‐29 cells but poorly, if at all observed, in the other cell types. In HT‐29 cells, HNF1A‐AS1 localized to the nucleus and was found to bind to the enhancer of zeste homolog 2 (EZH2, a member of PRC2 complex) and potentially form RNA–DNA triplexes with DNase 1 accessible sites in the HT‐29 genome. These activities of HNF1A‐AS1 may contribute to the oncogenic properties of this long non‐coding RNA.

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Hepatocyte nuclear factor HNF1A is a potential regulator in shaping the super‐enhancer landscape in colorectal cancer liver metastasis

Cited by 6 publications

References 59 publications

Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status

Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status

The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors

Differential expression of HNF1A and HNF1A‐AS1 in colon cancer cells

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