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APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE270361 | GEO | 2025/12/04

REPOSITORIES: GEO

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APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer [ChIP-seq]

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

APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer

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.

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APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer [RNA-seq]

Project description:APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer [RNA-seq]

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APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer [ChIP-seq]

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