Abstract 262: APOBEC4, a novel regulator of p53-dependent cell cycle arrest, senescence, and apoptosis

Abstract Introduction: The tumor suppressor protein p53 (p53) is a transcription factor that can transactivate downstream target genes like p21, PUMA, NOXA, BAX, and GADD45a to cause cell cycle arrest, senescence, apoptosis, and other biological processes. However, its function is frequently compromised in tumorigenesis, with approximately half of human cancers harboring mutations in the TP53 gene. Notably, even in cases retaining wild-type p53 (wtp53), it gets degraded or inhibited through various mechanisms, including, the overexpression of its E3 ubiquitin ligase MDM2. MDM2 antagonists such as Nutlin-3a are promising strategies to restore p53 function and suppress tumor growth. However, the factors/biomarkers regulating the efficacy of MDM2 antagonists and p53-mediated tumor suppression remain unclear. Identifying such factors and understanding their functions are important to develop optimal therapeutic strategies targeting p53. Experimental procedures: Through a human whole-genome shRNA library screen, we attempted to identify factors regulating p53-mediated tumor suppression by treating osteosarcoma U2OS cells with an MDM2 antagonist. This screening and subsequent validation identified APOBEC4 as a factor that is required for p53-mediated suppression of colony formation following Nultin-3a treatment. Summary of data: Knocking down APOBEC4 mitigated Nutlin-3a-induced activation of p53 as a transcription factor, as well as p53-mediated cell cycle arrest and apoptosis in multiple p53-proficient cancer cells. Cellular senescence induced by H2O2 was also reduced upon APOBEC4 knockdown. Moreover, APOBEC4 overexpression enhanced x-ray irradiation-induced apoptosis in a manner dependent on p53. Conclusion: Our data suggest that APOBEC4 is a novel regulator required for p53-dependent cell cycle arrest, cellular senescence, and apoptosis. Citation Format: Dipesh Thapa, Atul Ranjan, Elizabeth Thoenen, Alejandro Parrales, Shigeto Nishikawa, Jay Vivian, Tomoo Iwakuma. APOBEC4, a novel regulator of p53-dependent cell cycle arrest, senescence, and apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 262.