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<p>The p53<sup>R175H</sup> mutant, a prevalent hotspot mutation in the p53 tumor suppressor gene, is linked to adverse clinical outcomes due to its gain-of-function properties in malignancies. Despite high expression levels of p53<sup>R175H</sup> protein in human cancers, the underlying mechanisms for its accumulation remain inadequately understood. Here, we identify a previously uncharacterized long non-coding RNA, designated as <i>LFPM</i>, which specifically binds to the L2 loop of p53<sup>R175H</sup> via a defined loop domain, thereby stabilizing the oncoprotein. Notably, wild-type p53 suppresses <i>LFPM</i> transcription, whereas p53<sup>R175H</sup> escapes this repression, establishing a pathogenic positive feedback loop. Functionally, <i>LFPM</i> promotes p53<sup>R175H</sup>-driven tumorigenesis by enhancing cellular proliferation and ferroptosis resistance. Mechanistically, <i>LFPM</i> competitively disrupts the interaction between p53<sup>R175H</sup> and the E3 ubiquitin ligase RING1, thus shielding p53<sup>R175H</sup> from ubiquitin-mediated degradation. Clinically, elevated <i>LFPM</i> expression correlates with poorer survival, specifically in p53<sup>R175H</sup>-mutant cancers. Our work unveils a pivotal mechanism for mutant p53 stabilization and nominates the <i>LFPM</i>-p53<sup>R175H</sup> axis as a promising therapeutic target.</p>

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LFPM inhibition of RING1-mediated p53R175H degradation drives oncogenesis in p53R175H-mutant cancers

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Xingkai Li,
  • Bing Wang,
  • Zhen Wang,
  • Yue Li,
  • Yupei Li,
  • Yushun Gao,
  • Xianteng Wang

摘要

The p53R175H mutant, a prevalent hotspot mutation in the p53 tumor suppressor gene, is linked to adverse clinical outcomes due to its gain-of-function properties in malignancies. Despite high expression levels of p53R175H protein in human cancers, the underlying mechanisms for its accumulation remain inadequately understood. Here, we identify a previously uncharacterized long non-coding RNA, designated as LFPM, which specifically binds to the L2 loop of p53R175H via a defined loop domain, thereby stabilizing the oncoprotein. Notably, wild-type p53 suppresses LFPM transcription, whereas p53R175H escapes this repression, establishing a pathogenic positive feedback loop. Functionally, LFPM promotes p53R175H-driven tumorigenesis by enhancing cellular proliferation and ferroptosis resistance. Mechanistically, LFPM competitively disrupts the interaction between p53R175H and the E3 ubiquitin ligase RING1, thus shielding p53R175H from ubiquitin-mediated degradation. Clinically, elevated LFPM expression correlates with poorer survival, specifically in p53R175H-mutant cancers. Our work unveils a pivotal mechanism for mutant p53 stabilization and nominates the LFPM-p53R175H axis as a promising therapeutic target.