scholarly journals Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer

2020 ◽  
Author(s):  
Elias Orouji ◽  
Ayush T. Raman ◽  
Anand K. Singh ◽  
Alexey Sorokin ◽  
Emre Arslan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Synergistic Effects ◽  
Expression Patterns ◽  
Chromatin State ◽  
Patient Specific ◽  
Normal Tissues ◽  
Active Enhancer ◽  
Colorectal Cancer Progression ◽  
And Function

ABSTRACTThe extent and function of chromatin state aberrations during colorectal cancer (CRC) progression is not completely understood. Here, by comprehensive epigenomic characterization of 56 tumors, adenomas, and their matched normal tissues, we define the dynamics of chromatin states during the progression of colorectal cancer. H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumor-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was crucial for excessive proliferation. Consistently, combination of MEK plus bromodomain (BET) inhibition was found to have synergistic effects in CRC patient-derived xenograft (PDX) models. Probing inter-tumor heterogeneity, we identified four distinct enhancer subtypes (EpiC), three of which correlate well with previously defined transcriptomic subtypes (CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, and TGFβi) for three EPIC groups. Our data suggest that the dynamics of active enhancer underlies colorectal cancer progression and the patient-specific active enhancer patterns govern their unique gene expression patterns which can be leveraged for precision combination therapy.

scholarly journals Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322835
Author(s):  
Elias Orouji ◽  
Ayush T Raman ◽  
Anand K Singh ◽  
Alexey Sorokin ◽  
Emre Arslan ◽  
...  
Keyword(s):  
Tumour Progression ◽  
Synergistic Effects ◽  
Chromatin State ◽  
Patient Specific ◽  
Normal Tissues ◽  
Comprehensive Knowledge ◽  
Active Enhancer ◽  
Significant Survival ◽  
Colon Cancer Cell Lines ◽  
Survival Differences

ObjectiveEnhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.DesignWe performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.ResultsWe demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.ConclusionOur data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.

scholarly journals Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Marta Codrich ◽  
Emiliano Dalla ◽  
Catia Mio ◽  
Giulia Antoniali ◽  
Matilde Clarissa Malfatti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cell Model ◽  
Patient Specific ◽  
Driver Genes ◽  
Proteomic Data ◽  
Whole Exome ◽  
Molecular Stability ◽  
Culturing Conditions ◽  
Colorectal Cancer Progression

Abstract Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. Methods Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. Results Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on driver genes CRC-associated. Moreover, the targeted NGS approach confirmed that organoids faithfully recapitulated patients’ tumor tissue. Using RNA-seq experiments, we identified 5125 differentially expressed transcripts in tumor versus normal organoids at different time points, in which the PTEN pathway resulted of particular interest, as also confirmed by further phospho-proteomics analysis. Interestingly, we identified the PTEN c.806_817dup (NM_000314) mutation, which has never been reported previously and is predicted to be deleterious according to the American College of Medical Genetics and Genomics (ACMG) classification. Conclusion The crosstalk of genomic, transcriptomic and phosphoproteomic data allowed to observe that PDCOs recapitulate, at the molecular level, the tumor of origin, accumulating mutations over time that potentially mimic the evolution of the patient’s tumor, underlining relevant potentialities of this 3D model.

scholarly journals Long non-coding RNA AGER-1 inhibits colorectal cancer progression through sponging miR-182

2020 ◽  
Vol 35 (1) ◽  
pp. 10-18 ◽  
Author(s):  
Mingzhu Lin ◽  
Yinyan Li ◽  
Jianfeng Xian ◽  
Jinbin Chen ◽  
Yingyi Feng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Vital Role ◽  
Normal Tissues ◽  
Non Coding Rna ◽  
Colorectal Cancer Progression ◽  
And Migration ◽  
Long Non Coding Rna

Objective: Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Ectopic expression of a novel lncRNA, termed lnc-AGER-1, has been discovered in cancers, and this lncRNA was reported to exert an anti-tumor effect. However, its biological mechanism remains unelucidated in colorectal cancer. Methods: A total of 159 paired colorectal cancer specimens and adjacent tissues was applied to detect the expression of lnc-AGER-1 by the quantitative Real-time PCR (qRT-PCR), and a series of functional assays was executed to uncover the role of this lncRNA on colorectal cancer. Results: We found that the expression of lnc-AGER-1 in the tumor tissues was significantly down-regulated, while compared with adjacent normal tissues (0.0115 ± 0.0718 vs. 0.0347 ± 0.157; P < 0.0001). Also, lnc-AGER-1 was observably associated with clinical T status (r = −0.184, P = 0.024). Patients with advanced T status exerted a significantly lower level of lnc-AGER-1 than those with early T status (20.0% vs. 40.7%, P = 0.021). Over-expression of lnc-AGER-1 inhibited cell proliferation and migration efficiency, and induced cell cycle arrest at the G0/G1 phase, and promoted cell apoptosis. Further research proved that lnc-AGER-1 altered the expression of its neighbor gene, AGER, through acting as a competing endogenous RNA for miR-182 in colorectal cancer. Conclusion: lnc-AGER-1 has a suppressive role in colorectal cancer development via modulating AGER, which may serve as a target for colorectal cancer diagnosis and treatment.

scholarly journals Stabilization of UCA1 by N6-methyladenosine RNA methylation modification promotes colorectal cancer progression

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rong-Zhang He ◽  
Jing Jiang ◽  
Xinglin Hu ◽  
Ming Lei ◽  
Jia Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Rna Methylation ◽  
Normal Tissues ◽  
Qrt Pcr ◽  
Hct 116 ◽  
Colorectal Cancer Progression ◽  
Hct 116 Cells ◽  
The Stability

Abstract Background UCA1 is frequently upregulated in a variety of cancers, including CRC, and it can play an oncogenic role by various mechanisms. However, how UCA1 is regulated in cancer is largely unknown. In this study, we aimed to determine whether RNA methylation at N6-methyladenosine (m6A) can impact UCA1 expression in colorectal cancer (CRC). Methods qRT-PCR was performed to detect the level of UCA1 and IGF2BP2 in CRC samples. CRISPR/Cas9 was employed to knockout (KO) UCA1, METTL3 and WTAP in DLD-1 and HCT-116 cells, while rescue experiments were carried out to re-express METTL3 and WTAP in KO cells. Immunoprecipitation using m6A antibody was performed to determine the m6A modification of UCA1. In vivo pulldown assays using S1m tagging combined with site-direct mutagenesis was carried out to confirm the recognition of m6A-modified UCA1 by IGF2BP2. Cell viability was measured by MTT and colony formation assays. The expression of UCA1 and IGF2BP2 in TCGA CRC database was obtained from GEPIA (http://gepia.cancer-pku.cn). Results Our results revealed that IGF2BP2 serves as a reader for m6A modified UCA1 and that adenosine at 1038 of UCA1 is critical to the recognition by IGF2BP2. Importantly, we showed that m6A writers, METTL3 and WTAP positively regulate UCA1 expression. Mechanically, IGF2BP2 increases the stability of m6A-modified UCA1. Clinically, IGF2BP2 is upregulated in CRC tissues compared with normal tissues. Conclusion These results suggest that m6A modification is an important factor contributing to upregulation of UCA1 in CRC tissues.

scholarly journals MiR-532-3p suppresses colorectal cancer progression by disrupting the ETS1/TGM2 axis-mediated Wnt/β-catenin signaling

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Chuncai Gu ◽  
Jianqun Cai ◽  
Zhijun Xu ◽  
Shiming Zhou ◽  
Liangying Ye ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Therapy ◽  
Potential Candidate ◽  
Mesenchymal Transition ◽  
Plasma Microrna ◽  
Colorectal Cancer Progression ◽  
And Function ◽  
Canonical Wnt

Abstract The expression panel of plasma microRNA defined miR-532-3p as a valuable biomarker for colorectal adenoma (CRA). However, its expression pattern and function in colorectal cancer (CRC) have remained unclear. The present study investigated the expression levels of miR-532-3p and found that it was in situ downregulated both in CRA and CRC. Moreover, it functioned as a sensitizer for chemotherapy in CRC by inducing cell cycle arrest and early apoptosis via its activating effects on p53 and apoptotic signaling pathways. In addition, miR-532-3p was found to restrain cell growth, metastasis, and epithelial–mesenchymal transition (EMT) phenotype of CRC. A study on the mechanism behind these effects revealed that miR-532-3p directly binds to 3′UTR regions of ETS1 and TGM2, ultimately repressing the canonical Wnt/β-catenin signaling. Further investigation showed that TGM2 was transcriptionally regulated by ETS1 and ETS1/TGM2 axis served as a vital functional target of miR-532-3p in suppressing CRC progression. To conclude, miR-532-3p mimics could act as potential candidate for molecular therapy in CRC through inactivation of the canonical Wnt/β-catenin signaling and enhancement of chemosensitivity.

scholarly journals LncRNA MSC-AS1 Promotes Colorectal Cancer Progression by Regulating miR-325/TRIM14 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Changhong He ◽  
Xia Wang ◽  
Meichun Du ◽  
Yanjun Dong
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Expression Patterns ◽  
Inhibitory Effect ◽  
Tumor Promoter ◽  
Migration And Invasion ◽  
Western Blot Assay ◽  
Invasion And Migration ◽  
Cell Progression ◽  
Colorectal Cancer Progression

Background. LncRNA MSC-AS1 has been reported to be a tumor promoter in hepatocellular carcinoma. However, the function of MSC-AS1 in colorectal cancer (CRC) has not been elucidated. It is designed to study the expression level of MSC-AS1 and investigate its biological effect on the progression of CRC. Methods. The expression patterns of MSC-AS1, miR-325, and TRIM14 were explored by RT-qPCR in CRC tissues and cells. The protein expression of TRIM14 was tested by Western blot assay. The association between MSC-AS1 expression and clinicopathological data was analyzed by chi-squared test. CCK-8 assay, colony formation, and Transwell assay were used to investigate the effect of MSC-AS1 on cell growth, invasion, and migration in CRC cells. The correlations among MSC-AS1, miR-325, and TRIM14 were analyzed by Pearson’s correlation coefficient analysis. Results. We found that MSC-AS1 and TRIM14 were upregulated in CRC tissues, while miR-325 was downregulated in CRC tissues. Functional experiments demonstrated that MSC-AS1 knockdown inhibited cell proliferation, migration, and invasion abilities in CRC cells. Additionally, miR-325 was proved to be a target miRNA of MSC-AS1, and TRIM14 might be a downstream gene of miR-325. Besides that, MSC-AS1 counteracted the inhibitory effect of miR-325 on the cell progression and TRIM14 expression. Conclusion. Our results indicated that MSC-AS1 facilitated CRC progression by sponging miR-325 to upregulate TRIM14 expression. We suggested that MSC-AS1 might be a potential lncRNA-target for CRC therapy.

scholarly journals Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Fangfang Yang ◽  
Hua Wang ◽  
Bianbian Yan ◽  
Tong Li ◽  
Lulu Min ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Progression ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Aberrant Expression ◽  
Cell Migration And Invasion ◽  
Lovo Cells ◽  
Colorectal Cancer Progression

Abstract The molecular pathogenesis of colorectal cancer (CRC) has been widely investigated in recent years. Accumulating evidence has indicated that microRNA (miRNA) dysregulation participates in the processes of driving CRC initiation and progression. Aberrant expression of miR-1301 has been found in various tumor types. However, its role in CRC remains to be elucidated. In the present study, we identified miR-1301 was enriched in normal colorectal tissues and significantly down-regulated in CRC. Decreased level of miR-1301 strongly correlated with aggressive pathological characteristics, including advanced stage and metastasis. Bioinformatics and dual luciferase assay demonstrated that STAT3 is a direct target of miR-1301. Gain and loss-of-function assays showed that miR-1301 had no effect on cell proliferation. Overexpression of miR-1301 suppressed cell migration and invasion capacity of pSTA3-positive LoVo cells, but not pSTAT3-negative SW480 cells, while inhibition of miR-1301 consistently promoted cell migration and invasion in both cell lines. Additionally, miR-1301 inhibition restored the suppressed migration and invasion of STAT3- knockdown LoVo cells. MiR-1301 functioned as a tumor suppressor to modulate the IL6/STAT3 signaling pathway. In summary, this study highlights the significant role of miR- 1301/STAT3 axis in CRC metastasis.

scholarly journals Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xin Huang ◽  
Yichao Hou ◽  
Xiaoling Weng ◽  
Wenjing Pang ◽  
Lidan Hou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Copper Complex ◽  
Aerobic Glycolysis ◽  
Active Role ◽  
Downstream Effector ◽  
Glycolysis Pathway ◽  
Colorectal Cancer Progression

AbstractExploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis–mediated aerobic glycolysis pathway.

scholarly journals LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 195
Author(s):  
Francisca Dias ◽  
Cristina Almeida ◽  
Ana Luísa Teixeira ◽  
Mariana Morais ◽  
Rui Medeiros
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Progression ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Amino Acid Transporters ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Colorectal Cancer Progression ◽  
Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

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