scholarly journals Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Dingye Yu ◽  
Xiao Yang ◽  
Jianwei Lin ◽  
Zichao Cao ◽  
Chenghao Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Fate ◽  
Immune Evasion ◽  
Immune Escape ◽  
Rna Seq ◽  
Functional Studies ◽  
Expression Of Genes ◽  
Super Enhancer ◽  
Growth Of Tumor

Unveiling key oncogenic events in malignancies is the key to improving the prognosis and therapeutic outcome of malignancies. Lines of evidence have shown that super-enhancers control the expression of genes that determine the cell fate, but the oncogenic super-enhancers in colorectal cancer (CRC) and their impact on carcinogens remain largely unexplored. Here, we identified a new oncogenic super-enhancer-regulated gene, IL-20RA, in CRC. Using the integrative analysis of H3K27ac ChIP-seq and RNA-seq in CRC tumors and normal colon tissues, we obtained a series of oncogenic super-enhancers in CRC. We found that super-enhancer inhibition by JQ-1 or iBET-151 suppressed the growth of tumor cells and inhibited the expression of IL-20RA. We found that IL-20RA was highly expressed in the tumor tissue of CRC and related to the advanced stage. Further functional studies showed that knockdown of IL-20RA inhibited the growth and metastasis of CRC. In addition, we found that IL-20RA was involved in regulating oncogenic and immune pathways and affecting the expression of genes related to cell proliferation and immune evasion in CRC. Together, our study demonstrated a novel oncogene in CRC and shed new light on oncogenic super-enhancer contributions to cell proliferation and immune escape.

scholarly journals Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing-Lan Li ◽  
Xiang Lin ◽  
Ya-Li Yu ◽  
Lin Chen ◽  
Qi-Xin Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Cancer Patient ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Motif Analysis ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Genome Wide ◽  
Functional Factors ◽  
Cancer Tissues

AbstractColorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

scholarly journals Super-enhancer Associated Long Non-coding RNA AC005592.2 Promotes Tumor Progression by Regulating OLFM4 in Colorectal Cancer

2020 ◽  
Author(s):  
Linping Yan ◽  
Huanhuan Chen ◽  
Li Tang ◽  
Pan Jiang ◽  
Feng Yan
Keyword(s):  
Colorectal Cancer ◽  
Biological Effects ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Invasion And Migration ◽  
Super Enhancer ◽  
Non Coding Rna ◽  
Attractive Therapeutic Target ◽  
And Migration ◽  
Long Non Coding Rna

Abstract Background: Super-enhancer-associated long non-coding RNAs (SE-lncRNAs) have been reported to play essential roles in tumorigenesis, but the fundamental mechanism of SE-lncRNAs in colorectal cancer (CRC) remains largely unknown. Methods: A microarray was performed to identify the differentially expressed SE-lncRNAs between CRC tissues and peritumoral tissues. A novel SE-lncRNA AC005592.2 was selected from these differentially expressed SE-lncRNAs to explore its effects in the CRC development. Fluorescence quantitative real-time PCR (qRT-PCR) was used to assay the expression of AC005592.2 in CRC tissues and cell lines. Functional assays were applied to identify the biological effects of AC005592.2 in CRC cells. Furthermore, RNA-seq was employed to predict potential targets of AC005592.2. Results: AC005592.2 was significantly increased in CRC tissues and cells. And the high expression of AC005592.2 was significantly associated with TNM stage and tumor differentiation of CRC patients. Knockdown of AC005592.2 suppressed CRC cell proliferation, invasion and migration, but promoted apoptosis, while AC005592.2 overexpression exerted precisely the opposite effects on CRC cells. Besides, AC005592.2 positively regulated the expression of olfactomedin 4 (OLFM4), which was also up-regulation in CRC tissues. Conclusion: The findings suggested that AC005592.2 is a crucial promoter of CRC progression, and may serve as an attractive therapeutic target for CRC.

scholarly journals Taraxasterol acetate targets RNF31 to inhibit RNF31/p53 axis-driven cell proliferation in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chao-Tao Tang ◽  
Jing Yang ◽  
Zi-De Liu ◽  
Youxiang Chen ◽  
Chunyan Zeng
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Model ◽  
Tissue Samples ◽  
The Third ◽  
Common Cancer ◽  
A Cell ◽  
Growth Of Tumor

AbstractColorectal cancer (CRC) is the third most common cancer worldwide. Several studies have suggested that taraxasterol acetate (TA) can inhibit the growth of tumor cells. However, to date, it remains unclear how TA inhibits cell growth and how RNF31 functions as an oncogene. We examined the expression of RNF31 in CRC tissue samples via immunohistochemistry and elucidated the function of RNF31 in CRC cells by constructing a cell model with RNF31 depletion. A cycloheximide (CHX)-chase analysis and immunofluorescence assays were conducted to demonstrate that TA can promote RNF31 degradation by activating autophagy. We used the PharmMapper website to predict targets of TA and identified RNF31. CHX-chase experiments showed that TA could facilitate RNF31 degradation, which was inhibited by the administration of chloroquine. Immunofluorescence assays showed that RNF31 protein was colocalized with LC3I/II and p62, suggesting that TA promoted RNF31 degradation by activating autophagy. We also found that CRC patients with RNF31 overexpression had poorer survival than those with low RNF31 expression. The results of the CHX-chase experiment showed that depletion of RNF31 alleviated p53 degradation, which was inhibited by MG132. A series of co-immunoprecipitation (Co-IP) assays revealed that RNF31 interacts with p53 and promotes p53 ubiquitination and degradation. A Co-IP assay performed with a truncated RNF31 plasmid showed that the PUB domain interacts with p53. Moreover, the PUB domain is the key structure in the induction of p53 ubiquitination. Our findings reveal a key role of RNF31 in CRC cell growth and indicate a mechanism through which TA inhibits cell growth.

scholarly journals Genome-wide profiling of active enhancers in colorectal cancer

2020 ◽  
Author(s):  
Min Wu ◽  
Qinglan Li ◽  
Xiang Lin ◽  
Ya-Li Yu ◽  
Lin Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Whole Genome ◽  
Cancer Cell Migration ◽  
Rna Seq ◽  
Motif Analysis ◽  
Super Enhancer ◽  
Genome Wide ◽  
The World ◽  
Functional Factors ◽  
Oncogenic Transcription Factor

Abstract Colorectal cancer (CRC) is one of the most common cancers in the world. Although genomic mutations and SNPs have been extensively studied, the epigenomic status in CRC patient tissues remains elusive. Here, we profiled active enhancers genome-widely in paired CRC patient tissues through H3K27ac ChIP-Seq, together with genomic and transcriptomic analysis. Totally we sequenced 73 pairs of CRC tissues and generated 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq files. Our analysis discovered 5590 gain variant enhancer loci (VEL) and 1100 lost VELs in CRC, and 334 gain variant super enhancer loci (VSEL) and 121 lost VSELs. Multiple key transcription factors in CRC were predicted with motif analysis and core regulatory circuitry analysis. Further experiments verified the functions of 6 super enhancers governing PHF19, LIF, SLC7A5, CYP2S1, RNF43 and TBC1D16 in regulating cancer cell migration, and we identified KLF3 as a novel oncogenic transcription factor in CRC. Taken together, our work provides important epigenomic resource and novel functional factors for epigenetic studies in CRC.

scholarly journals Super-enhancer-associated long noncoding RNA AC005592.2 promotes tumor progression by regulating OLFM4 in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Linping Yan ◽  
Huanhuan Chen ◽  
Li Tang ◽  
Pan Jiang ◽  
Feng Yan
Keyword(s):  
Colorectal Cancer ◽  
Noncoding Rna ◽  
Biological Effects ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Invasion And Migration ◽  
Super Enhancer ◽  
Attractive Therapeutic Target ◽  
And Migration ◽  
Fundamental Mechanism

Abstract Background Super-enhancer-associated long noncoding RNAs (SE-lncRNAs) have been reported to play essential roles in tumorigenesis, but the fundamental mechanism of SE-lncRNAs in colorectal cancer (CRC) remains largely unknown. Methods A microarray was performed to identify the differentially expressed SE-lncRNAs between CRC tissues and peritumoral tissues. A novel SE-lncRNA, AC005592.2, was selected from these differentially expressed SE-lncRNAs to explore its effects on CRC development. Fluorescence quantitative real-time PCR (qRT-PCR) was used to assay the expression of AC005592.2 in CRC tissues and cell lines. Functional assays were applied to identify the biological effects of AC005592.2 in CRC cells. Furthermore, RNA-seq was employed to predict potential targets of AC005592.2. Results AC005592.2 was significantly increased in CRC tissues and cells. High expression of AC005592.2 was significantly associated with TNM stage and tumor differentiation in CRC patients. Knockdown of AC005592.2 suppressed CRC cell proliferation, invasion and migration but promoted apoptosis, while AC005592.2 overexpression exerted the opposite effects on CRC cells. In addition, AC005592.2 positively regulated the expression of olfactomedin 4 (OLFM4), which was also upregulated in CRC tissues. Conclusion The findings suggested that AC005592.2 is a crucial promoter of CRC progression and may serve as an attractive therapeutic target for CRC.

Kidney collecting duct acid-base “regulon”

2006 ◽  
Vol 27 (3) ◽  
pp. 271-281 ◽  
Author(s):  
Lydie Cheval ◽  
Luciana Morla ◽  
Jean-Marc Elalouf ◽  
Alain Doucet
Keyword(s):  
Cell Proliferation ◽  
Metabolic Acidosis ◽  
Collecting Duct ◽  
Acid Base Balance ◽  
Acid Base ◽  
Functional Studies ◽  
Expression Of Genes ◽  
Base Balance ◽  
Medullary Collecting Duct ◽  
Acid Base Disturbance

Kidneys are essential for acid-base homeostasis, especially when organisms cope with changes in acid or base dietary intake. Because collecting ducts constitute the final site for regulating urine acid-base balance, we undertook to identify the gene network involved in acid-base transport and regulation in the mouse outer medullary collecting duct (OMCD). For this purpose, we combined kidney functional studies and quantitative analysis of gene expression in OMCDs, by transcriptome and candidate gene approaches, during metabolic acidosis. Furthermore, to better delineate the set of genes concerned with acid-base disturbance, the OMCD transcriptome of acidotic mice was compared with that of both normal mice and mice undergoing an adaptative response through potassium depletion. Metabolic acidosis, achieved through an NH4Cl-supplemented diet for 3 days, not only induced acid secretion but also stimulated the aldosterone and vasopressin systems and triggered cell proliferation. Accordingly, metabolic acidosis increased the expression of genes involved in acid-base transport, sodium transport, water transport, and cell proliferation. In particular, >25 transcripts encoding proteins involved in urine acidification (subunits of H-ATPase, kidney anion exchanger, chloride channel Clcka, carbonic anhydrase-2, aldolase) were co-regulated during acidosis. These transcripts, which cooperate to achieve a similar function and are co-regulated during acidosis, constitute a functional unit that we propose to call a “regulon”.

scholarly journals MSTN mutant promoted bovine muscle satellite cell proliferation by regulating the binding of SMAD2/SMAD3 with CDKN1C

2021 ◽  
Author(s):  
Li Gao ◽  
Miao-Miao Yang ◽  
Ming-Juan Gu ◽  
Yun-Peng Liu ◽  
Cai-Hong Bu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Chromatin Immunoprecipitation ◽  
Muscle Development ◽  
Chip Assay ◽  
Rna Seq ◽  
Wild Type ◽  
Muscle Satellite Cell ◽  
Bovine Muscle ◽  
Expression Of Genes

Abstract Background: Myostatin (MSTN), also known as growth/differentiation factor 8, mostly expressed in skeletal muscle and plays negative roles in regulation of muscle development. Previous studies had proved that MSTN have important effect on cell proliferation. Therefore we aimed to investigate the mechanism of MSTN in regulating the proliferation of bovine muscle satellite cells (MSCs).Methods: Bovine MSCs of MSTN mutant (MT) and wild type (WT) were obtained, we detected the cell proliferation and cell cycle by EdU proliferation assay and Flow cytometry. Then we detected the expression of genes associated with cell cycle by Real-time PCR and Western blotting . RNA-seq and Chromatin immunoprecipitation (ChIP)assay were performed to research the mechanism of MSTN in regulating the cell proliferation. Results: In this study, we found that MSTN mutant promoted the proliferation of MSCs. The expression of CyclinA, CyclinD and CyclinE were all increased after MSTN mutant, while the expression of CDKN1C (P57), CDKN2A, CDKN2C and CDKN2D were down-regulated, which were consistent with the promotion of cell proliferation. Among these genes, CDKN1C(P57) down-regulated most significantly. RNA-seq results showed that MSTN mutant affected the SMAD binding, so we performed ChIP-qPCR and demonstrated that the SMAD2/SMAD3 transcription factor combined with the promoter of CDKN1C thus to increase the expression of CDKN1C, this demonstrating that MSTN regulated the expression of CDKN1C through SMAD2/SMAD3 complex. Finally, overexpression of SMAD3 in wild type cells increased the expression of CDKN1C, further suggested that SMAD3 regulated the expression of CDKN1C. Conclusion: MSTN mutant down-regulated the expression of SMAD2/SMAD3, then reduced the promotion of SMAD2/SMAD3 to the expression of CDKN1C, thus to inhibit the expression of CDKN1C, then promoting the cell cycle.

scholarly journals S100A9 Derived From Myeloma Associated Myeloid Cells Promotes TNFSF13B/TNFRSF13B-Dependent Proliferation and Survival of Myeloma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Lingzhang Meng ◽  
Qiang Tang ◽  
Jingjie Zhao ◽  
Zechen Wang ◽  
Liuzhi Wei ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Bone Marrow Cells ◽  
Animal Experiments ◽  
Myeloid Cells ◽  
Myeloma Cell ◽  
Rna Seq ◽  
Myeloma Cells ◽  
Dependent Cell

Multiple myeloma (MM) is a lethal hematological malignancy characterized by abundant myeloid cells in the microenvironment that fuel tumor progression. But the mechanism by which myeloid cells support myeloma cells has not been fully explored. We aimed to examine their effect on bone marrow cells of MM patients by scRNA-seq transcriptome analysis and reveal a high-resolution gene profile of myeloma cells and myeloma-associated myeloid cells. Based on correlation analysis of integrated scRNA-seq and bulk RNA-seq datasets from patients, we confirmed that myeloid-derived S100A9 was involved in TNFSF13B-dependent myeloma cell proliferation and survival. In the animal experiments, S100A9 was found to be critical for MM cell proliferation and survival via TNFSF13B production by myeloid cells, neutrophils, and macrophages. In-vitro analysis of patient primary myeloma cells further demonstrated that enhanced TNFSF13B signaling triggered the canonical NF-κB pathway to boost tumor cell proliferation. All these results suggest that myeloid-derived S100A9 is required for TNFSF13B/TNFRSF13B-dependent cell-fate specification, which provides fresh insights into MM progression.

scholarly journals AXIN2 reduces the survival of porcine induced pluripotent stem cells (piPSCs)

2021 ◽  
Author(s):  
rui zhang ◽  
Shuai Yu ◽  
Qiaoyan Shen ◽  
Wenxu Zhao ◽  
Juqing Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Pluripotent Stem Cells ◽  
Culture Medium ◽  
Wnt Signaling Pathway ◽  
Rna Seq ◽  
Expression Of Genes ◽  
Induced Pluripotent ◽  
Effect Of Inhibitors

Abstract BackgroundThe establishment of porcine pluripotent stem cells (piPSCs) is still a critical topic and challenging issue. However, all piPSCs are extremely sensitive to changes of the culture conditions.In addition, the side effect of inhibitors in culture medium confine the pluripotency and practicability. This study aimed to investigate the roles of AXIN in piPSCs and further explore the mechanism. Here, porcine AXIN1 gene and AXIN2 were knockdown, cloned, and overexpressed in piPSCs. Digital RNA-seq was performed to explore the mechanism of cell proliferation and anti-apoptosis. ResultsHere, we found (1): overexpression of the porcine AXIN2 gene significantly reduce the survivability of piPSCs, meanwhile wreck the pluripotency of piPSCs; (2): The Digital RNA-seq analysis reveals that AXIN2, as a negative effector of the WNT signaling pathway, whom after knockdown enhances the expression of genes involved in cell cycle such as CCND1, and reduced the expression of genes related to cell differentiation, cell death, and cell apoptosis. ConclusionAXIN2 could reduce the pluripotency and survival of piPSCs and also provided a potential to simplify the cultrue medium.

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