| First Author | Guo B | Year | 2024 |
| Journal | Neoplasia | Volume | 53 |
| Pages | 101005 | PubMed ID | 38761506 |
| Mgi Jnum | J:352616 | Mgi Id | MGI:7707561 |
| Doi | 10.1016/j.neo.2024.101005 | Citation | Guo B, et al. (2024) Enhanced Apc(Min/+) adenoma formation after epithelial CUL4B deletion by recruitment of myeloid-derived suppressor cells. Neoplasia 53:101005 |
| abstractText | Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing Apc(Min/+) mice with Cul4b(DeltaIEC) mice to achieve specific deletion of Cul4b in the gut epithelium against an Apc(Min/+) background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited Apc(Min/+) adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted Apc(Min/+) adenomas. Furthermore, the addition of MDSCs to in vitro cultured Apc(Min/+); Cul4b(DeltaIEC) adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating Apc(Min/+) adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling. |
