Differential RNA-seq analysis comparing APC-defective and APC-restored SW480 colorectal cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76307 | GEO | 2016/02/01
SECONDARY ACCESSION(S): PRJNA306863
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC4778681 | biostudies-literature
Project description:The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals, and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC Analysis of RNA isolated from colon polyps that presented in shAPC or shAPC/Kras mice as compared to shRenilla (neutral) mouse colon mucosa
2015-06-18 | E-GEOD-67186 | biostudies-arrayexpress
Project description:Mutations in the tumor suppressor APC initiate CRC in part by preventing the GSK3 kinase from phosphorylating β-CATENIN, leading to its stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well-established, APC regulation of GSK3 activity upon other targets with potential oncogenic relevance are not understood. Here, we identify the H4K20 methyltransferase SETD8 as target of APC-coordinated GSK3 phosphorylation in the intestinal epithelium. We found that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, loss of SETD8 phosphorylation in tumors results in a loss of H4K20me1 deposition at oncogenic cholesterol biosynthesis and fetal intestinal genes, allowing for their activation at least in part through gain of YAP accessibility. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN-independent oncogenic consequence of APC loss.
2025-12-11 | GSE313053 | GEO
Project description:The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals, and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC
2015-06-18 | GSE67186 | GEO
Project description:Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths with increasing incidence globally. Mutations in the tumor suppressor APC initiate CRC at least in part by preventing the GSK3 kinase from phosphorylating β-CATENIN, leading to its constitutive stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well-established, APC regulation of GSK3 activity upon other targets with potential oncogenic relevance are not understood. Here, we identify the H4K20 methyltransferase SETD8 as target of GSK3 phosphorylation requiring functional APC in the intestinal epithelium. We found that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, phosphorylation alters the role of SETD8 in transcriptional regulation, most notably by preventing it from activating oncogenic YAP signaling and an oncogenic fetal-like transcriptional program. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN -independent oncogenic consequence of APC loss.
2025-12-04 | GSE270360 | GEO
Project description:Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths with increasing incidence globally. Mutations in the tumor suppressor APC initiate CRC at least in part by preventing the GSK3 kinase from phosphorylating β-CATENIN, leading to its constitutive stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well-established, APC regulation of GSK3 activity upon other targets with potential oncogenic relevance are not understood. Here, we identify the H4K20 methyltransferase SETD8 as target of GSK3 phosphorylation requiring functional APC in the intestinal epithelium. We found that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, phosphorylation alters the role of SETD8 in transcriptional regulation, most notably by preventing it from activating oncogenic YAP signaling and an oncogenic fetal-like transcriptional program. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN -independent oncogenic consequence of APC loss.
2025-12-04 | GSE270361 | GEO
Project description:Wnt signaling plays a pivotal role in colorectal cancer. Intrinsic activation of Wnt by mutational events, such as mutations in the tumor suppressor gene APC, represents the most frequent initiating event in this disease background. Long truncated versions of APC retain partial functionality, which leads to a sub-maximal, “just right” activation state of Wnt signaling supposed to be beneficial for disease initiation. In order to study the transcriptomic alterations of an over-stimulated Wnt signaling pathway, conditional shRNA-mediated silencing of APC was performed in chromosomal instable HT-29 CRC cells which express a 1555 amino acid variant of APC protein able to bind and partially inactivate β-catenin. To achieve this, cells were stably transduced with lentiviral particles encoding for a doxycyline-inducible shRNA directed against APC, or, as a control, a non-silencing shRNA (pTRIPZ inducible shRNA vectors, RHS4740-EG324, Horizon Dharmacon, CO, USA). 72 hours after APC silencing, total RNA was isolated and quality controlled for subsequent RNA-Seq Analysis (DKFZ Heidelberg, Genomic and Proteomic Core Facility) on a HiSeq 2000 instrument (Illumina). Overall, we observed bona-fide Wnt target genes, such as NKD1, AXIN2, PTK7, ASCL2, and SMOC2, and additional putative direct or indirect targets of Wnt signaling up-regulated upon shRNA-mediated APC silencing.
2020-06-25 | GSE131575 | GEO
Project description:We show that single agent treatment with either cobimetinib or APC restoration, results in cell plasticity.
2026-04-05 | GSE301561 | GEO
Project description:APC is a classical tumor suppressor in humans, and truncating mutations are early somatic events in most cases of sporadic colon cancer. APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and therefore loss of full length APC reduces GSK-3 activity, leading to stabilization of b-catenin protein and activation of downstream Wnt/b-catenin signaling. GSK-3 also phosphorylates multiple core mRNA splicing factors and loss of Gsk3a/b in mouse ES cells and human lymphocytes alters mRNA splicing at a genome wide level. We therefore predict that loss of APC should similarly alter splicing by reducing GSK-3 activity. Here we use RNA-seq to assess differential gene expression and altered splicing in apc-mcr mutant zebrafish embryos at 48hpf. We find robust activation of known Wnt/b-catenin target genes, as expected. Surprisingly, we also find markedly increased expression of multiple genes related to inflammation and cytokine signaling. We also identify 340 mRNA splicing variations in apc mutant zebrafish. Many of these local splice variants (LSVs) occur in mRNAs the regulate cell adhesion, migration, and morphogenesis.
2023-06-19 | GSE234986 | GEO
Project description:We show that single agent treatment with either divarasib (KRAS G12Ci) or APC restoration, results in cell plasticity.
2026-04-05 | GSE301559 | GEO