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Publications

Journal Article Ahead of print

PubMed: 42387064 DOI: 10.1038/s41418-026-01805-7

LFPM inhibition of RING1-mediated p53 R175H degradation drives oncogenesis in p53 R175H-mutant cancers.

Cell Death Differ

Authors: Xingkai Li, Bing Wang, Zhen Wang, Yue Li, Yupei Li, Yushun Gao, Xianteng Wang

Affiliations

  • Molecular Cancer Research Center, Zhongshan School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Department of Anesthesiology, Peking University Third Hospital, Beijing, China.
  • Molecular Cancer Research Center, Zhongshan School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China.
  • Molecular Cancer Research Center, Zhongshan School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-Sen University, Shenzhen, China.

Abstract

The p53 R175H 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 R175H 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 p53 R175H via a defined loop domain, thereby stabilizing the oncoprotein. Notably, wild-type p53 suppresses LFPM transcription, whereas p53 R175H escapes this repression, establishing a pathogenic positive feedback loop. Functionally, LFPM promotes p53 R175H-driven tumorigenesis by enhancing cellular proliferation and ferroptosis resistance. Mechanistically, LFPM competitively disrupts the interaction between p53 R175H and the E3 ubiquitin ligase RING1, thus shielding p53 R175H from ubiquitin-mediated degradation. Clinically, elevated LFPM expression correlates with poorer survival, specifically in p53 R175H-mutant cancers. Our work unveils a pivotal mechanism for mutant p53 stabilization and nominates the LFPM-p53 R175H axis as a promising therapeutic target.

MeSH

Genes, Cell Differentiation, Ubiquitin, Neoplasms, Genes, P53, Carcinogenesis, Ubiquitin-Protein Ligases, Cell Death