C1Q + TPP1 + macrophages promote colon cancer progression through SETD8-driven p53 methylation.

In many tumors, the tumor suppressor TP53 (p53) is not mutated, but experiences functional inactivation. Notwithstanding, restoring p53 function emerges as an appealing therapeutic approach for tumors exhibiting wild-type p53 (p53WT). However, the mechanisms underlying the functional inactivation of p53 in these tumors remain poorly understood. Previously, we identified SETD8 as a critical suppressor of p53 activity in neuroblastomas. SETD8 is the sole known enzyme that mono-methylates p53 on lysine 382 (p53K382me1), resulting in the inhibition of its pro-apoptotic and growth-arresting functions. In this study, we observed high expression levels of SETD8 and p53K382me1 in 185 colorectal cancer (CRC) tissue samples, being negatively associated with patient survival probability. Significantly, the expression of p53K382me1 resulted confined to colorectal cancer stem cells and tumor-associated macrophages (TAM) in tissues obtained from CRC patients. Within CRC patient cohorts, high expression of p53K382me1 levels in both stem and immune cells predict decreased survival probability. The SETD8-mediated inactivation of p53 through p53K382me1 may serve as an early requirement for tumor initiation, particularly in inflammation-induced cancers, and as a functional biomarker and therapeutic target in advanced CRCs