GEO series

APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer

GSE313053 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2025/12/11 Platform GPL24247

Summary

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.

Published in

Cramer Z, Monaghan K, Petroni R et al. · Cell reports 2026 · PMID 41790555 · doi:10.1016/j.celrep.2026.117045

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Direct links to NCBI, no account and no request form: the whole study as GSE313053_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 4 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1378195 and SRA study SRP653795. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41790555) ↗

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