FTO downregulation mediated by hypoxia facilitates colorectal cancer metastasis.
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ABSTRACT:
SUBMITTER: Ruan DY
PROVIDER: S-EPMC8376648 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Fatty acid oxidation (FAO) has been proven to be an accomplice in tumor progression. Carnitine palmitoyltransferase 1C (CPT1C), a rate-limiting enzyme in FAO, mainly functions to catalyze fatty acid carnitinylation and guarantee subsequent entry into the mitochondria for FAO in colorectal cancer (CRC). Gene expression data and clinical information extracted from The Cancer Genome Atlas (TCGA) database show significantly higher expression of CPT1C in patients with metastatic CRC ( P=0.005). Moreover, overexpression of CPT1C is correlated with worse relapse-free survival in CRC (HR 2.1, P=0.0006), while no statistical significance is indicated for CPT1A and CPT1B. Further experiments demonstrate that downregulation of CPT1C expression leads to a decrease in the FAO rate, suppression of cell proliferation, cell cycle arrest and repression of cell migration in CRC, whereas opposite results are obtained when CPT1C is overexpressed. Furthermore, an FAO inhibitor almost completely reverses the enhanced cell proliferation and migration induced by CPT1C overexpression. In addition, analysis of TCGA data illustrates a positive association between CPT1C expression and HIF1α level, suggesting that CPT1C is a transcriptional target of HIF1α. In conclusion, CPT1C overexpression indicates poor relapse-free survival of patients with CRC, and CPT1C is transcriptionally activated by HIF1α, thereby promoting the proliferation and migration of CRC cells.
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Project description:Background: Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis. Method: The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by in vivo lung and liver metastatic models. Results: The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis. Conclusion: Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.
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Project description:Inflammation is frequently associated with initiation, progression, and metastasis of colorectal cancer (CRC). Here, we unveil a CRC-specific metastatic programme that is triggered via the transcriptional repressor, GFI1. Using data from a large cohort of clinical samples including inflammatory bowel disease and CRC, and a cellular model of CRC progression mediated by cross-talk between the cancer cell and the inflammatory microenvironment, we identified GFI1 as a gating regulator responsible for a constitutively activated signalling circuit that renders CRC cells competent for metastatic spread. Further analysis of mouse models with metastatic CRC and human clinical specimens reinforced the influence of GFI1 downregulation in promoting CRC metastatic spread. The novel role of GFI1 is uncovered for the first time in a human solid tumour such as CRC. Our results imply that GFI1 is a potential therapeutic target for interfering with inflammation-induced CRC progression and spread.
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Project description:BackgroundFeminization-1 (FEM-1) is considered a substrate recognition subunit of CUL2-RING E3 ubiquitin ligase complexes, which refers to sex determination by modulating TRA-1 stability in C. elegans. The function of mammalian orthologous gene of FEM-1 remains to be elucidated.MethodsThe expression of FEM1C in colorectal cancer (CRC) cells was interfered by small interference RNA (siRNA) transfection, and Cell counting kit-8 (CCK-8) assay, colony formation assay and transwell assay were performed. In order to estimate the function on metastasis, stable knockdown FEM1C cells were used to established liver and lung metastasis models. In addition, the expression of FEM1C in normal tissues, adenomas and tumor tissues were analyzed, and the relationship between FEM1C expression level and prognosis was analyzed by Kaplan-Meier method.ResultsHere, we report that the elimination of FEM1C, one of the members of FEM-1, significantly promoted the migration and invasion of colorectal cancer (CRC) cells in vitro and promoted liver and lung metastases in vivo. It also showed that the removal of FEM1C improved the proliferation ability of CRC cells. In particular, the cell shape changed from epithelial to fibroblast-like morphology. The tight cell monolayer was transformed into a dispersed distribution. Furthermore, it was demonstrated that FEM1C is down-regulated in tissues of CRC compared to normal tissues, and the high expression of FEM1C positively correlates with a good prognosis in patients with CRC. GSEA analysis showed that EMT signatures was enriched in FEM1C knockdown groups.ConclusionsDown-regulation of FEM1C promotes proliferation and metastasis, and FEM1C may be a tumor suppressor in the development of CRC.
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Project description:Hypoxia is an extensively investigated condition due to its contribution to various pathophysiological processes including cancer progression and metastasis formation. MicroRNAs (miRNAs) are well-known post-transcriptional gene expression regulators. However, their contribution to molecular response to hypoxia is highly dependent on cell/tissue types and causes of hypoxia. One of the most important examples is colorectal cancer, where no consensus on hypoxia-regulated miRNAs has been reached so far. In this work, we applied integrated mRNA and small RNA sequencing, followed by bioinformatics analysis, to study the landscape of hypoxia-induced miRNA and mRNA expression alterations in human colorectal cancer cell lines (HT-29 and Caco-2). A hypoxic microenvironment was chemically modeled using two different treatments: cobalt(II) chloride and oxyquinoline. Only one miRNA, hsa-miR-210-3p, was upregulated in all experimental conditions, while there were nine differentially expressed miRNAs under both treatments within the same cell line. Further bioinformatics analysis revealed a complex hypoxia-induced regulatory network: hypoxic downregulation of hsa-miR-148a-3p led to the upregulation of its two target genes, ITGA5 and PRNP, which was shown to be a factor contributing to tumor progression and poor survival in colorectal cancer patients.
| S-EPMC8202010 | biostudies-literature
Project description:Kinesin family member 4A (KIF4A) was found to be implicated in the regulation of chromosome condensation and segregation during mitotic cell division, which is essential for eukaryotic cell proliferation. However, little is known about the role of KIF4A in colorectal carcinoma (CRC). This study explored the biological function of KIF4A in CRC progression and investigated the potential molecular mechanisms involved. Here, we found that KIF4A was remarkably upregulated in primary CRC tissues and cell lines compared with paired non-cancerous tissues and normal colorectal epithelium. Elevated expression of KIF4A in CRC tissues was significantly correlated with clinicopathological characteristics in patients as well as with shorter overall and disease-free cumulative survival. Multivariate Cox regression analysis revealed that KIF4A was an independent prognostic factor for poor survival in human CRC patients. Functional assays, including a CCK-8 cell proliferation assay, colony formation analysis, cancer xenografts in nude mice, cell cycle and apoptosis analysis, indicated that KIF4A obviously enhanced cell proliferation by promoting cell cycle progression in vitro and in vivo. Furthermore, gene set enrichment analysis, Luciferase reporter assays, and ChIP assays revealed that KIF4A facilitates cell proliferation via regulating the p21 promoter, whereas KIF4A had no effect on cell apoptosis. In addition, Transwell analysis indicated that KIF4A promotes migration and invasion in CRC. Taken together, these findings not only demonstrate that KIF4A contributes to CRC proliferation via modulation of p21-mediated cell cycle progression but also suggest the potential value of KIF4A as a clinical prognostic marker and target for molecular treatments.
| S-EPMC5924760 | biostudies-literature
Project description:Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is a major leading of death in patients with CRC and many patients have metastatic disease at diagnosis. However, the underlying molecular mechanisms are still elusive. Here, we showed that JMJD1C was overexpressed in colon cancer tissues compared to normal samples and was positively associated with metastasis and poor prognosis. Silencing JMJD1C strongly inhibits CRC migration and invasion both in vitro and in vivo. Further, we found that knockdown of JMJD1C decreased the protein and mRNA levels of ATF2, mechanistically, and JMJD1C regulated the expression of ATF2 by modulating the H3K9me2 but not H3K9me1 activity. In addition, we further performed some "rescues experiments". We found that overexpression of ATF2 could reverse the abrogated migration and invasion ability by knockdown of JMJD1C in CRC. Our results demonstrated that an increase of JMJD1C was observed in colon cancer and knockdown of JMJD1C regulated CRC metastasis by inactivation of the ATF2 pathway. This novel JMJD1C/ATF2 signaling pathway may be a promising therapeutic target for CRC metastasis.
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Project description:Phenotypic conversion of tumor cells through epithelial-mesenchymal transition (EMT) requires massive gene expression changes. How these are brought about is not clear. Here we examined the impact of the EMT master regulator SNAIL1 on the FOXA family of transcription factors which are distinguished by their particular competence to induce chromatin reorganization for the activation of transcriptional enhancer elements. We show that the expression of SNAIL1 and FOXA genes is anticorrelated in transcriptomes of colorectal tumors and cell lines. In cellular EMT models, ectopically expressed Snail1 directly represses FOXA1 and triggers downregulation of all FOXA family members, suggesting that loss of FOXA expression promotes EMT. Indeed, cells with CRISPR/Cas9-induced FOXA-deficiency acquire mesenchymal characteristics. Furthermore, ChIP-seq data analysis of FOXA chromosomal distribution in relation to chromatin structural features which characterize distinct states of transcriptional activity, revealed preferential localization of FOXA factors to transcriptional enhancers at signature genes that distinguish epithelial from mesenchymal colon tumors. To validate the significance of this association, we investigated the impact of FOXA factors on structure and function of enhancers at the CDH1, CDX2 and EPHB3 genes. FOXA-deficiency and expression of dominant negative FOXA2 led to chromatin condensation at these enhancer elements. Site-directed mutagenesis of FOXA binding sites in reporter gene constructs and by genome-editing in situ impaired enhancer activity and completely abolished the active chromatin state of the EPHB3 enhancer. Conversely, expression of FOXA factors in cells with inactive CDX2 and EPHB3 enhancers led to chromatin opening and de novo deposition of the H3K4me1 and H3K27ac marks. These findings establish the pioneer function of FOXA factors at enhancer regions of epithelial genes and demonstrate their essential role in maintaining enhancer structure and function. Thus, by repressing FOXA family members, SNAIL1 targets transcription factors at strategically important positions in gene-regulatory hierarchies, which may facilitate transcriptional reprogramming during EMT.
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Project description:BackgroundUTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear.MethodsImmunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses.ResultsHerein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression.ConclusionsIn the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.
| S-EPMC10483726 | biostudies-literature
Project description:Cancer cell-derived extracellular vesicles (EVs) have been reported to promote the progression of colorectal cancer (CRC), although the regulatory mechanism remains uncharacterized. In this study, we investigated the role of microRNA-25 (miR-25)/sirtuin 6 (SIRT6) in the contribution of EVs derived from CRC cells to progression of CRC. In a co-culture system with EVs from HCT116 and NCM460 cells, the viability, migratory, and invasive properties of SW480 and SW620 cells were evaluated by cell counting kit-8 (CCK-8) and Transwell assays. Luciferase, chromatin immunoprecipitation (ChIP), and RNA immunoprecipitation (RIP) assays were conducted to verify the interaction among miR-25, SIRT6, lin-28 homologB (Lin28b), and neuropilin-1 (NRP-1). It was established that HCT116 cell-derived EVs promoted the malignant properties of SW480 cells and SW620 cells by delivering miR-25. SIRT6 was targeted by miR-25, whereas SIRT6 inhibited NRP-1 through downregulation of Lin28b. The tumor-bearing nude mouse experiments substantiated that HCT116 cell-derived EVs transferred miR-25 to facilitate tumor formation and metastasis by inhibiting SIRT6. In summary, our study clarifies the involvement of miR-25-targeted SIRT6 inhibition and SIRT6-mediated inhibition of the Lin28b/NRP-1 axis in CRC cell-derived EVs to CRC progression and metastasis.
| S-EPMC7810909 | biostudies-literature