LFPM Inhibition of RING1-Mediated p53R175H Degradation Drives Oncogenesis in p53R175H-Mutant Cancers

The p53R175H mutant, a prevalent hotspot mutation in the p53 tumor suppressor gene, is associated with poor clinical outcomes due to its gain-of-function activities in cancer. Despite high expression levels of p53R175H protein in human cancers, the underlying mechanisms for its accumulation remain elusive. Here, we identify a previously uncharacterized long non-coding RNA, which we renamed LFPM, that interacts specifically with p53R175H, excluding the wild-type p53, and modulates its protein stability. This interaction is mediated through the DNA-binding domain of p53R175H and a specific loop region within LFPM. The stabilization of p53R175H by LFPM contributes to the gain-of-function activities associated with this mutant, including enhanced cell proliferation and resistance to ferroptosis. Mechanistically, LFPM disrupts the RING1-p53R175H interaction, thereby preventing RING1-mediated ubiquitination and proteasomal degradation of p53R175H. Clinically, elevated LFPM expression correlates with poor survival in p53R175H-mutant tumors. Our findings suggest that targeting the LEFM-p53R175H axis may offer a therapeutic strategy for cancers with p53R175H mutations, highlighting the potential of LFPM as a biomarker and therapeutic target.