Abstract 2377: Impairment of p53-activating pathways accelerates liver cancer initiation partially through MTHFD1L-mediated 1C metabolism

Abstract

Abstract Hepatocellular carcinoma (HCC) takes several decades to develop from premalignant lesions in chronically damaged livers and is often detected at a later stage; thus, prevention is of particular importance. HCC originates from differentiated hepatocytes. Previous studies have shown that inhibition of the tumor suppressor p53 is required for the differentiated hepatocytes to acquire the features that are needed for their conversion to HCC progenitor cells (HcPCs). However, the initiation of p53 response to de-differentiation of damaged hepatocytes is largely unclear. p53 is tightly controlled by MDM2 and MDMX. We and others have previously demonstrated that multiple stresses can trigger the binding of 14-3-3 to phosphorylated MDMX, or ribosomal proteins L5 and L11 to MDM2, to further disrupt the MDMX- or MDM2-p53 association and lead to p53 activation. This was validated by two animal models, MDM2C305F and MDMX3SA knock-in mice that are defective in 14-3-3-MDMX and L5/L11-MDM2 interactions, respectively. By crossing these two mouse lines, we generated a double knock-in (DKI) mouse line. With this line, we found that carcinogen DEN-induced HCC occurrence is significantly higher in MDM2C305F-MDMX3SA -DKI mice, and HcPCs isolated from DEN-treated DKI mice display significantly more stem cell- and malignancy- properties and higher tumorigenesis when introduced into mouse livers. Furthermore, we found that MTHFD1L, a monofunctional tetrahydrofolate synthase required for mitochondrial 1-carbon (1C) metabolism, is transcriptionally suppressed by p53 and exerts a critical effect on the accelerated HCC initiation in DKI mice. Taken together, these results demonstrate a crucial role of these two p53-activating pathways in preventing HCC initiation by controlling the mitochondrial 1C- metabolism. Citation Format: Yiwei Zhang, Yitian Zha, Hua Lu. Impairment of p53-activating pathways accelerates liver cancer initiation partially through MTHFD1L-mediated 1C metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2377.