Abstract 4778: FOXR2 reverses MDM2-mediated but not MDM4-mediated p53 repression

Abstract Despite advances in therapy, cancer remains a major health challenge in the 21st century, with mortality rate ranging from approximately 11% to 25%. The tumor suppressor p53, a protein critical for cancer development and prevention, is regulated by numerous interacting partners. In our previous unpublished findings, we identified that FOXR2 (an epigenetically regulated pan-cancer oncogene) is able to module p53 activity. Consequently, in the present investigation, we broaden our exploration to examine how FOXR2 regulates p53 transactivation. We first found that FOXR2 enhances p53 transactivation in a dose-dependent manner in H1299 (p53 NULL) cells. Given that MDM2 and MDM4 (MDMX) are major p53 negative regulators, we then tested whether FOXR2 could counteract MDM2- and MDM4-mediated p53 repression. We found that FOXR2 dose-dependently reverses MDM2-mediated p53 transactivation. However, FOXR2 has minimal or no effect on MDM4-mediated p53 repression. Moreover, our data suggests that FOXR2 is capable of binding to p53. Finally, we found that FOXR2 increases wild-type (WT) p53, but not G245S (hotspot mutation) p53, transactivation. Taken together, our preliminary results demonstrate that FOXR2 is a novel protein to regulate p53 activity likely involving MDM2 competition due to possible p53-FOXR2 interaction. This data is presented to substantiate the concept that p53’s activity is governed by a complex and still-expanding network of interactions. Citation Format: Wei-Hsiung Yang, Anmol P. Patel, William H. Yang. FOXR2 reverses MDM2-mediated but not MDM4-mediated p53 repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4778.