Abstract p53 is a transcription factor that regulates the expression of target genes involved in anti-proliferative processes such as cell cycle arrest, apoptosis, and senescence, thereby establishing its canonical role as a tumor suppressor. Due to its substantial network of target genes, p53 is also involved in non-canonical tumor suppression pathways that are yet to be fully explored. During the search of these pathways, we identified one of the methyltransferases as a novel p53 target gene. It’s been reported that this methyltransferase is downregulated in various cancers, suggesting potential tumor suppressive function. However, the specific target of this methyltransferase and its role in the mechanism of p53-mediated tumor suppression remains elusive. In this study, we show that p53 directly binds to intron 1 of this methyltransferase gene and activates its transcription and protein expression. Furthermore, we identify dihydrolipoic acid (DHLA), an important redox cofactor, as a novel target of this methyltransferase. We show that this methyltransferase enhances cellular sensitivity to oxidative stress-induced cell death by potentially methylating DHLA. Our studies reveal a novel role for p53 in regulating the well-known antioxidant DHLA to control cell death and suggest potential therapeutic strategies in promoting cancer cell death through p53 activation drugs. Citation Format: Fatima Alaydaroos, Yoko Itahana, Koji Itahana. p53-induced Methyltransferase Increases Cancer Cell Vulnerability to Cell Death abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P18.
Alaydaroos et al. (Fri,) studied this question.