scholarly journals PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Bing Yao ◽  
Tao Gui ◽  
Xiangwei Zeng ◽  
Yexuan Deng ◽  
Zhi Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Intervention Strategy ◽  
Dependent Manner ◽  
Egfr Signaling ◽  
Colon Cells ◽  
Atpase Subunit ◽  
Cellular Analysis ◽  
Colorectal Cancer Progression

Abstract Background Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood. Methods In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression. Results We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-ApcMin/+ CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC. Conclusion PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.

scholarly journals MiR-629-5p promotes colorectal cancer progression through targetting CXXC finger protein 4

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Jinlai Lu ◽  
Shuirong Lu ◽  
Jingze Li ◽  
Qi Yu ◽  
Lang Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Cell Apoptosis ◽  
Tumor Promoter ◽  
Finger Protein ◽  
Cell Proliferation And Migration ◽  
Colorectal Cancer Progression ◽  
And Migration ◽  
Proliferation And Migration

MiR-629-5p has been shown to function as a tumor promoter in some types of cancer. However, the role of miR-629-5p in colorectal cancer remains unclear. Here, the significant up-regulation of miR-629-5p in colorectal cancer tissues and cell lines was observed. Overexpression of miR-629-5p showed a positive effect on cell proliferation and migration. The enhanced miR-629-5p level also suppressed cell apoptosis and resulted in a low Bax level and a high Bcl-2 level. Further down-regulating miR-629-5p demonstrated opposite effects. CXXC finger protein 4 (CXXC4) was predicted as a direct target of miR-629-5p. Dual-luciferase reporter and Western blotting assays exhibited miR-629-5p directly bound to the 3′UTR of CXXC4 and then down-regulated its expression at post-transcriptional level. CXXC4 knockdown rescued the decreased cell proliferation and migration and the enhanced cell apoptosis induced by inhibiting miR-629-5p expression. Notably, overexpression of miR-629-5p also conferred 5-fluorouracil sensitivity, which was partly abrogated by coexpression of CXXC4. Overall, the results presented here suggest that miR-629-5p functions as a tumor promoter by improving proliferation and migration and repressing apoptosis and 5-FU sensitivity in colorectal cancer progression by directly down-regulating CXXC4.

scholarly journals Meprinα Transactivates the Epidermal Growth Factor Receptor (EGFR) via Ligand Shedding, thereby Enhancing Colorectal Cancer Cell Proliferation and Migration

2012 ◽  
Vol 287 (42) ◽  
pp. 35201-35211 ◽  
Author(s):  
Petra Minder ◽  
Elke Bayha ◽  
Christoph Becker-Pauly ◽  
Erwin E. Sterchi
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cancer Progression ◽  
Cell Proliferation And Migration ◽  
Epidermal Growth ◽  
Colorectal Cancer Progression ◽  
And Migration ◽  
Proliferation And Migration

Meprinα, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinα in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinα activity at primary tumor sites. A role for meprinα in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinα-mediated transactivation of the EGFR signaling pathway and suggest that this mechanism is involved in colorectal cancer progression. Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprinα is capable of shedding epidermal growth factor (EGF) and transforming growth factor-α (TGFα) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinα. The physiological effects of meprinα-mediated shedding of EGF and TGFα were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprinα leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinα in the EGFR/MAPK signaling pathway indicates a role of meprinα in colorectal cancer progression.

scholarly journals LINC01224 promotes colorectal cancer progression through targeting miR-485-5p/MYO6 axis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingfeng Gu ◽  
Liang Dong ◽  
Yun Wang ◽  
Wenjia Nie ◽  
Wencong Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Binding Interaction ◽  
Tissue Samples ◽  
Rna Immunoprecipitation ◽  
Colorectal Cancer Progression ◽  
Transcription Factor Yy1

Abstract Background Long noncoding RNAs (lncRNAs) are related to colorectal cancer (CRC) development. However, the role and mechanism of lncRNA LINC01224 in CRC development are largely unknown. Methods LINC01224, Yin Yang 1 (YY1), microRNA (miR)-485-5p, and myosins of class VI (MYO6) levels were examined using quantitative reverse transcription polymerase chain reaction and western blotting. Functional analyses were processed through CCK-8, colony formation, flow cytometry, transwell, and xenograft analyses. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation, and pull-down assays were conducted to analyze the binding interaction. Results LINC01224 abundance was elevated in CRC tissue samples and cell lines. Elevated LINC01224 might indicate the lower 5-year overall survival in 52 CRC patients. LINC01224 was upregulated via the transcription factor YY1. LINC01224 knockdown restrained CRC cell proliferation, migration, and invasion and increased apoptosis. MiR-485-5p was sponged by LINC01224, and miR-485-5p downregulation relieved the influence of LINC01224 interference on CRC progression. MYO6 was targeted via miR-485-5p and regulated via LINC01224/miR-485-5p axis. MiR-485-5p overexpression suppressed CRC cell proliferation, migration, and invasion and facilitated apoptosis. MYO6 upregulation mitigated the role of miR-485-5p. LINC01224 knockdown decreased xenograft tumor growth. Conclusion YY1-induced LINC01224 regulates CRC development via modulating miR-485-5p/MYO6 axis.

scholarly journals Natural podophyllotoxin analog 4DPG attenuates EMT and colorectal cancer progression via activation of checkpoint kinase 2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Archana Katoch ◽  
Debasis Nayak ◽  
Mir Mohd. Faheem ◽  
Aviral Kumar ◽  
Promod Kumar Sahu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Checkpoint Kinase ◽  
Mesenchymal Transition ◽  
Checkpoint Kinase 2 ◽  
Clinical Benefits ◽  
Colorectal Cancer Progression

AbstractEpithelial–mesenchymal transition (EMT) is critical for the metastatic dissemination of cancer cells and contributes to drug resistance. In this study, we observed that epithelial colorectal cancer (CRC) cells transiently exposed to 5-fluorouracil (5-FU) (a chemotherapeutic drug for CRC) as well as 5-FU-resistant cells (5-FU-R) develop EMT characters as evidenced by activation of Vimentin and augmented invasive properties. On the other hand, 4DPG (4′-demethyl-deoxypodophyllotoxin glucoside), a natural podophyllotoxin analog attenuates EMT and invadopodia formation abilities of HCT-116/5-FU-R and SW-620/5-FU-R cells. Treatment with 4DPG restrains Vimentin phosphorylation (Ser38) in 5-FU-R cells, along with downregulation of mesenchymal markers Twist1 and MMP-2 while augmenting the expression of epithelial markers E-cadherin and TIMP-1. Moreover, 4DPG boosts the tumor-suppressor protein, checkpoint kinase 2 (Chk2) via phosphorylation at Thr68 in a dose-dependent manner in 5-FU-R cells. Mechanistically, SiRNA-mediated silencing of Chk2, as well as treatment with Chk2-specific small-molecule inhibitor (PV1019), divulges that 4DPG represses Vimentin activation in a Chk2-dependent manner. Furthermore, immunoprecipitation analysis unveiled that 4DPG prevents complex formation between Vimentin and p53 resulting in the rescue of p53 and its nuclear localization in aggressive 5-FU-R cells. In addition, 4DPG confers suitable pharmacokinetic properties and strongly abrogates tumor growth, polyps formation, and lung metastasis in an orthotopic rat colorectal carcinoma model. In conclusion, our findings demonstrate 4DPG as a targeted antitumor/anti-metastatic pharmacological lead compound to circumvent EMT-associated drug resistance and suggest its clinical benefits for the treatment of aggressive cancers.

scholarly journals MiR-137 Targets the 3′ Untranslated Region of MSH2: Potential Implications in Lynch Syndrome-Related Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4662
Author(s):  
Raffaella Liccardo ◽  
Raffaele Sessa ◽  
Silvia Trombetti ◽  
Marina De Rosa ◽  
Paola Izzo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Lynch Syndrome ◽  
Molecular Mechanisms ◽  
Genome Instability ◽  
Cell Cycle Control ◽  
Site Directed Mutagenesis ◽  
Dependent Manner ◽  
Colon Cells ◽  
Sw480 Cells

Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are unknown. One such gene, MSH2, exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control. In this study, we explored the functions and underlying molecular mechanisms of increased MSH2 expression related to a c.*226A>G variant in the 3′untranslated (UTR) region of MSH2 that had been previously identified in a subject clinically suspected of LS. Bioinformatics identified a putative binding site for miR-137 in this region. To verify miRNA targeting specificity, we performed luciferase gene reporter assays using a MSH2 3′UTR psiCHECK-2 vector in human SW480 cells over-expressing miR-137, which showed a drastic reduction in luciferase activity (p > 0.0001). This effect was abolished by site-directed mutagenesis of the putative miR-137 seed site. Moreover, in these cells we observed that miR-137 levels were inversely correlated with MSH2 expression levels. These results were confirmed by results in normal and tumoral tissues from the patient carrying the 3′UTR c.*226A>G variant in MSH2. Finally, miR-137 overexpression in SW480 cells significantly suppressed cell proliferation in a time- and dose-dependent manner (p < 0.0001), supporting a role for MSH2 in apoptosis and cell proliferation processes. Our findings suggest miR-137 helps control MSH2 expression via its 3′UTR and that dysregulation of this mechanism appears to promote tumorigenesis in colon cells.

scholarly journals Long non-coding RNA TUSC7 suppressed colorectal cancer progression via regulation of miR-23b/PDE7A Axis

2020 ◽  
Vol 43 (4) ◽  
pp. E35-43
Author(s):  
Lingfang Hao ◽  
Yaofeng Yun ◽  
Run Liang ◽  
Gang Yuan
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Luciferase Reporter ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Progression

Purpose: Despite advances in our understanding of the roles of the long noncoding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) in cancer biology, which has been identified to act as a tumor suppressor by regulating cell proliferation, apoptosis, migration, invasion, cell cycle and tumor growth, its function in colorectal cancer remains unknown. Methods: The expression levels of TUSC7 in colorectal cancer tissues and cell lines were determined, and the biological functions of TUSC7 to cancer progression in colorectal cancer were investigated via correlation analysis of clinical samples, cell viability assay, transwell assay and apoptosis analysis. Further, the molecular regulatory mechanisms of TUSC7 were demonstrated by luciferase reporter assay and western blotting. Results: We observed that the expression of TUSC7 was markedly decreased in colorectal cancer cell lines. Moreover, the lower expression of TUSC7 was correlated with advanced clinical grades and poorer survival and may be an independent risk factor for colorectal cancer. Moreover, the expression of TUSC7 inhibited cell proliferation, invasion and epithelial-to-mesenchymal transition (EMT), while it facilitated apoptosis through competitively binding miR-23b. We also found that TUSC7 decreased the expression of phosphodiesterase 7A (PDE7A), a downstream target of miR-23b, through the TUSC7/miR-23b/PDE7A axis. Conclusion: We demonstrated the expression of TUSC7 suppressed colorectal cancer progression through the TUSC7/miR-23b/PDE7A axis, suggesting that TUSC is a potential target for therapeutic intervention in colorectal cancer.

scholarly journals STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer

2021 ◽  
Vol 22 (14) ◽  
pp. 7695
Author(s):  
Yael Delgado-Ramirez ◽  
Itzel Baltazar-Perez ◽  
Yamileth Martinez ◽  
Blanca E. Callejas ◽  
Itzel Medina-Andrade ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Tumor Formation ◽  
Intestinal Cell ◽  
Arginase 1 ◽  
Colorectal Cancer Progression ◽  
Oxide Synthase

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.

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