High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

Ren, Bo; Yang, Jinshou; Wang, Yuming; Ye, Gang; Wang, Huanyu; Yuan, Chen; Xu, Ruiyuan; Fan, Xu-Ning; You, Lei; Zhang, Taiping; Zhao, Yupei

doi:10.1186/s13045-021-01131-0

Cited by 39 publications

(36 citation statements)

References 40 publications

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“…Therefore, we investigated changes in 3D chromatin architecture using Hi-C. We generated 600 million reads per condition with biological replicates of the CTL, and replicates of CTCF +/− 1 and 2 were merged for high-resolution analysis. This sequencing depth allowed us to reach complete genomic coverage at a 5-kb resolution, consistent with previous high-resolution Hi-C data ( 43 , 44 ). Statistical analysis of the correlation between the contact matrices of each cell line revealed a marked difference between the CTL and both CTCF +/− clones at 5-kb resolution ( Fig.…”

Section: Resultssupporting

confidence: 86%

“…Here, we generated 600 million reads per condition with biological replicates of the WT, CTCF+/-#1 and #2 merged for high resolution analysis. This sequencing depth allowed us to reach a complete genomic coverage at 5kb resolution, consistent with previous high-resolution Hi-C data [57][58][59] . Genomewide, the megabase scale chromatin interactions in our WT cells (Supplementary Figure 6a) were strikingly consistent with previously published data 60 .…”

Section: Reduced Ctcf Levels Lead To Loss Of Insulation Of Subtad Str...supporting

confidence: 84%

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3D chromatin remodeling potentiates transcriptional programs driving cell invasion

Lebeau

Jangal

Zhao

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.

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Section: Resultssupporting

confidence: 86%

Section: Reduced Ctcf Levels Lead To Loss Of Insulation Of Subtad Str...supporting

confidence: 84%

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

Lebeau

Jangal

Zhao

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Synthesized in the endoplasmic reticulum of liver parenchymal cells, LIPC containing N-linked high mannose type was transferred to Golgi and secreted as an active form [24]. Based on previous studies, LIPC plays a disparate function in different cancers [12][13][14][15][16]. In our study, the protein and mRNA levels of LIPC were both downregulated in HCC, and it was important to note that there was a significant correlation between the downregulation of LIPC expression and the clinicopathological traits of HCC patients, including tumor size, tumor amounts, differentiation grade, AFP level, and BCLC stage.…”

Section: Discussionmentioning

confidence: 99%

“…LIPC is highly expressed in a cohort of human hepatic metastasis and primary colorectal tumors [ 13 , 14 ]. In addition, LIPC promotes the epithelial–mesenchymal transition (EMT) process in Borrmann type 4 gastric cancer [ 15 ] and pancreatic cancer [ 16 ]. It is indicated that LIPC is associated with tumor metastasis.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of TUSC3 promotes EMT and hepatocellular carcinoma progression through LIPC/AKT axis

Deng

Chen

et al. 2022

J Transl Med

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Background Hepatocellular carcinoma (HCC) is one of the most common and malignant tumors in the digestive tract. Tumor Suppressor Candidate 3 (TUSC3) is one subunit of the endoplasmic reticulum Oligosaccharyl transferase (OST) complex, which plays an important role in N-glycosylation during the protein folding process. However, the role of TUSC3 in the initiation and progression of HCC has not been mentioned yet. In the present study, we aim to investigate the effects of TUSC3 on the initiation and progression of HCC. Methods Immunohistochemical assay and qRT-PCR were used to detect the expression of TUSC3 and lipase C hepatic type (LIPC) in HCC tissue and cells. Loss-of-function and gain-of-function were applied to detect the function of TUSC3 and LIPC in vivo and in vitro. Immunofluorescence assay and co-immunoprecipitation were used to detect the relationship between TUSC3 and LPC. Western blot was applied to detect the expression of epithelial–mesenchymal transition (EMT) markers and the Akt signaling pathway. Results TUSC3 was aberrantly decreased in hepatocellular carcinoma tissues compared to the matched adjacent normal tissues, which resulted in bigger size of tumor (P = 0.001, Table 2), worse differentiation (P = 0.006, Table 2) and an advanced BCLC stage. Down-regulation of TUSC3 led to the enhanced proliferation and migration of hepatocellular carcinoma cells in vivo and vitro, whereas the opposite effect could be observed in the TUSC3-overexpression group. The analysis of TUSC3 microarray showed that LIPC, a glycoprotein primarily synthesized and secreted by hepatocytes, was a downstream target of TUSC3, and it negatively modulated the development of HCC. The morphological changes in HCC cells indicated that TUSC3 regulated the epithelial-mesenchymal transition (EMT). Mechanistically, TUSC3 inhibited EMT progression through the LIPC/AKT axis. Conclusion Down-regulation of TUSC3 promotes EMT progression by activating AKT signaling via targeting LIPC in HCC, which is probably the possible mechanism driving TUSC3-deficient hepatocellular carcinoma cells toward a malignant phenotype.

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“…Western blot analysis was performed as described previously [ 33 ]. The blot was cut prior to hybridisation with antibodies during blotting.…”

Section: Methodsmentioning

confidence: 99%

Construction of immune-related signature and identification of S100A14 determining immune-suppressive microenvironment in pancreatic cancer

et al. 2022

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Pancreatic cancer (PC) is a highly lethal and aggressive disease with its incidence and mortality quite discouraging. A robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Since the critical role of immune microenvironment in the progression of PC, a prognostic signature based on seven immune-related genes was established, which was validated in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set and GSE71729 set. Furthermore, S100A14 (S100 Calcium Binding Protein A14) was identified as the gene occupying the most paramount position in risk signature. According to the GSEA, CIBERSORT and ESTIMATE algorithm, S100A14 was mainly associated with lower proportion of CD8 + T cells and higher proportion of M0 macrophages in PC tissue. Meanwhile, analysis of single-cell dataset CRA001160 revealed a significant negative correlation between S100A14 expression in PC cells and CD8 + T cell infiltration, which was further confirmed by tissue microenvironment landscape imaging and machine learning-based analysis in our own PUMCH cohort. Additionally, analysis of a pan-pancreatic cancer cell line illustrated that S100A14 might inhibit CD8 + T cell activation via the upregulation of PD-L1 expression in PC cells, which was also verified by the immunohistochemical results of PUMCH cohort. Finally, tumor mutation burden analysis and immunophenoscore algorithm revealed that patients with high S100A14 expression had a higher probability of responding to immunotherapy. In conclusion, our study established an efficient immune-related prediction model and identified the potential role of S100A14 in regulating the immune microenvironment and serving as a biomarker for immunotherapy efficacy prediction.

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High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

Cited by 39 publications

References 40 publications

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

Downregulation of TUSC3 promotes EMT and hepatocellular carcinoma progression through LIPC/AKT axis

Construction of immune-related signature and identification of S100A14 determining immune-suppressive microenvironment in pancreatic cancer

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