APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality.
• Mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor are key initiators of CRC.
• APC loss stabilizes β-CATENIN, promoting mitogenic gene transcription, but its regulation of other GSK3 targets remains unclear.

Purpose of the Study:

• To identify novel targets of APC-regulated GSK3 phosphorylation in the intestinal epithelium.
• To investigate the role of SETD8 phosphorylation in colorectal cancer pathogenesis.
• To elucidate the molecular mechanisms linking APC loss, SETD8, and oncogenic gene activation.

Main Methods:

• Utilized mouse models of intestinal tumorigenesis.
• Investigated protein-protein interactions and phosphorylation events.
• Performed gene expression analysis and chromatin immunoprecipitation (ChIP).
• Assessed YAP protein accessibility to target genes.

Main Results:

• Identified SETD8, a H4K20 methyltransferase, as a target of APC-coordinated GSK3 phosphorylation.
• Demonstrated that GSK3 phosphorylation restrains the oncogenic activity of SETD8.
• Showed that loss of SETD8 phosphorylation sensitizes mice to oncogenic insults.
• Found that loss of SETD8 phosphorylation leads to decreased H4K20me1 at oncogenic genes, facilitating their activation via increased YAP accessibility.
• Highlighted a novel β-CATENIN-independent mechanism of APC loss in CRC.

Conclusions:

• SETD8 phosphorylation by GSK3 is a critical mechanism for restraining its oncogenic function in the intestinal epithelium.
• APC loss contributes to CRC through a β-CATENIN-independent pathway involving dysregulation of SETD8 and subsequent gene activation.
• Targeting SETD8 or related pathways may offer novel therapeutic strategies for colorectal cancer.