LINC00261 Suppresses Epithelial-Mesenchymal Transition and Metastatic Potential of Colorectal Cancer by Down-regulating the MeCP2-ZEB1 Feedback Loop
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ABSTRACT:
PROVIDER: PRJNA925459 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23118778_1.fastq.gz | Fastqsanger.gz | |||
| SRR23118778_2.fastq.gz | Fastqsanger.gz | |||
| SRR23118779_1.fastq.gz | Fastqsanger.gz | |||
| SRR23118779_2.fastq.gz | Fastqsanger.gz | |||
| SRR23118780_1.fastq.gz | Fastqsanger.gz |
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Project description:Accumulating evidence suggests that epithelial-mesenchymal transition (EMT) contributes to metastasis, a major cause of death in patients with colorectal cancer (CRC). MeCP2 (methyl CpG binding protein 2), a key modulator for initiating gene transcription, plays a pivotal role in EMT, but its upstream signaling pathways are poorly understood. We collected 137 colorectal cancer patients’ samples, including tumor tissues (n=137), adjacent normal tissues (n=137) and liver metastases (n=11). Three pairs of colorectal cancer cell lines were sequenced to identify high abundance of lincRNAs in primary tumor tissues. Two independent experiments (electrophoretic mobility shift assay and RNA immunoprecipitation assay) were used to characterize the interaction between LINC00261 and MeCP2. Subsequently, the effects of LINC00261 on phosphorylation of MeCP2 and promotion of the MeCP2-ZEB1 feedback were examined. Consequently long intergenic non-protein coding RNA 261 (LINC00261) was down-regulated in highly metastatic CRC cells and liver metastases from patients with CRC. Down-regulating LINC00261 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple CRC cell lines. Furthermore, knocking down LINC00261 increased colon-derived liver metastasis in an orthotopic CRC model and promoted distant metastatic colonization in a lung metastasis model. Mechanistic studies revealed that LINC00261 interacted with MeCP2 and stabilized it in the nucleus by inhibiting Ser80 phosphorylation Interestingly, ZEB1 could re-modulate MeCP2 expression by binding to the MeCP2 promoter, and they formed a positive feedback loop consequently. In contrast, the lower LINC00261 expression in CRC samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. Taken together, LINC00261 suppresses EMT and CRC cells’ metastatic potential by negatively regulating the MeCP2-ZEB1 feedback loop; LINC00261’s loss in metastatic tissues may be a potential prognostic marker of aggressive disease.
2024-12-31 | GSE223243 | GEO
Project description:To the best of our knowledge, this is the first study presenting detailed evidences for the underlying role of LINC00261 in pancreatic cancer both in vitro and in vivo. Also, we thoroughly explored the clinical value of LINC00261 in multicenter cohorts and developed an individualized predictive model of survival. To investigate the potential downstream pathway of LINC00261, we performed RNA-seq using two PANC-1 cell groups: LINC00261 knockdown and control.
2023-06-08 | GSE152012 | GEO
Project description:Lung cancer is the leading cause of cancer-related death in the United States. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules whose role in lung carcinogenesis is poorly understood. In this study, we profiled lncRNA expression in lung adenocarcinoma (LUAD) cell lines, compared their expression to that of purified alveolar epithelial type II cells (the purported cell of origin for LUAD), cross-referenced these with lncRNAs altered in primary human tumors, and interrogated for lncRNA whose expression correlated with patient survival. We identified LINC00261, a lncRNA with unknown function in LUAD, adjacent to the pioneering transcription factor FOXA2. Loss of LINC00261 was observed in multiple tumor types, including liver, breast, and gastric cancer. Reintroduction of LINC00261 into human LUAD cell lines inhibited cell migration and slowed proliferation by inducing a G2/M cell cycle arrest while upregulating DNA damage pathway genes and inducing phosphorylation-mediated activation of components of the DNA damage pathway. FOXA2 was able to induce LINC00261 expression, and the entire locus underwent hypermethylation in LUAD, leading to loss of expression. We have thus identified an epigenetically deregulated lncRNA, whose loss of expression in LUAD promotes the malignant phenotype and blocks activation of the DNA damage machinery, predisposing lung cells to cancer development.
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Project description:BackgroundBreast cancer has become the most frequently diagnosed cancer worldwide. Increasing evidence indicated that zinc finger proteins (ZNFs), the largest family of transcription factors, contribute to cancer development and progression. Although ZNF384 is overexpressed in several types of human cancer, the role of ZNF384 in breast cancer remains unknown. Therefore, our research focused on ZNF384 regulation of the malignant phenotype of breast cancer and the underlying molecular mechanisms.MethodsCCK-8 and colony formation assays were used to evaluate cell proliferation. Transwell and scratch assays were used to evaluate the cell migration and invasion. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were used to confirm the target relationship between ZNF384 and zinc finger E-box binding homeobox 1 (ZEB1). Xenografts were used to monitor the targets in vivo effects.ResultsWe noted that ZNF384 was significantly overexpressed in breast cancer and highlighted the oncogenic mechanism of ZNF384. ZNF384 transactivated ZEB1 expression and induced an epithelial and mesenchymal-like phenotype, resulting in breast cancer metastasis. Furthermore, ZNF384 may be a target of miR-485-5p, and ZEB1 can up-regulate ZNF384 expression by repressing miR-485-5p expression. Together, we unveiled a feedback loop of ZNF384-ZEB1 in breast cancer metastasis.ConclusionsThe findings suggest that ZNF384 can serve as a prognostic factor and a therapeutic target for breast cancer patients.
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Project description:MECP2-R270X transgenic mice (TG) and MECP2-G273X TG mice were generated in the Zoghbi Lab. These mice express the respective truncated form of MeCP2 tagged with GFP at the C-terminus from a transgenic human PAC containing all known regulatory sequences. These transgenes were maintained on a wild-type pure FVB background. For experiments each transgenic line was crossed by Mecp2 null mice (Mecp2 tm1.1Bird) on a pure 129SvEv background and the resulting male F1 hybrid progeny (FVB;129SvEv) that lacked endogenous MeCP2 expression but expressed either transgene (Mecp2 -/y; MECP2-R270X TG or Mecp2-/y; MECP2-G273X TG) were used for ChIP-Seq analysis. Whole brain from either the R270X mice (Mecp2 -/y; MECP2-R270X TG) or the G273X mice (Mecp2 -/y; MECP2-G273X TG) was formaldehyde crosslinked and purified chromatin was immunoprecipitated with anti-GFP antibody (Abcam ab6556). 2 samples: R270X (Mecp2 -/y; MECP2-R270X TG) and G273X (Mecp2 -/y; MECP2-G273X TG) both on an F1 (FVB;129SvEv) hybrid background
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Project description:MeCP2 globally regulates gene expression in the brain. One example is Growth-differentiation factor 11 (Gdf11), which is down-regulated upon loss of MeCP2 and up-regulated upon gain of MeCP2. To assess if MeCP2 binds near the Gdf11 locus we performed CUT&RUN for MeCP2 in Mecp2-knockout or MECP2-transgenic hippocampus. To assess if a repressive histone modification (H3K27me3) was concordantly changed we profiled H3k27me3 in these same matched tissues.
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Project description:MECP2-R270X transgenic mice (TG) and MECP2-G273X TG mice were generated in the Zoghbi Lab. These mice express the respective truncated form of MeCP2 tagged with GFP at the C-terminus from a transgenic human PAC containing all known regulatory sequences. These transgenes were maintained on a wild-type pure FVB background. For experiments each transgenic line was crossed by Mecp2 null mice (Mecp2 tm1.1Bird) on a pure 129SvEv background and the resulting male F1 hybrid progeny (FVB;129SvEv) that lacked endogenous MeCP2 expression but expressed either transgene (Mecp2 -/y; MECP2-R270X TG or Mecp2-/y; MECP2-G273X TG) were used for ChIP-Seq analysis. Whole brain from either the R270X mice (Mecp2 -/y; MECP2-R270X TG) or the G273X mice (Mecp2 -/y; MECP2-G273X TG) was formaldehyde crosslinked and purified chromatin was immunoprecipitated with anti-GFP antibody (Abcam ab6556).
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Project description:Methylation mediated LINC00261 suppresses pancreatic cancer progression
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Project description:MeCP2 and H3K27me3 binding in Mecp2-knockout and MECP2-transgenic hippocampus
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Project description:Lung cancer is the leading cause of cancer-related death in the United States. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules whose role in lung carcinogenesis is poorly understood. In this study, we profiled lncRNA expression in lung adenocarcinoma (LUAD) cell lines, compared their expression to that of purified alveolar epithelial type II cells (the purported cell of origin for LUAD), cross-referenced these with lncRNAs altered in primary human tumors, and interrogated for lncRNA whose expression correlated with patient survival. We identified LINC00261, a lncRNA with unknown function in LUAD, adjacent to the pioneering transcription factor FOXA2. Loss of LINC00261 was observed in multiple tumor types, including liver, breast, and gastric cancer. Reintroduction of LINC00261 into human LUAD cell lines inhibited cell migration and slowed proliferation by inducing a G2/M cell cycle arrest while upregulating DNA damage pathway genes and inducing phosphorylation-mediated activation of components of the DNA damage pathway. FOXA2 was able to induce LINC00261 expression, and the entire locus underwent hypermethylation in LUAD, leading to loss of expression. We have thus identified an epigenetically deregulated lncRNA, whose loss of expression in LUAD promotes the malignant phenotype and blocks activation of the DNA damage machinery, predisposing lung cells to cancer development.
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