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

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• The p53^R175H mutation is a common hotspot mutation in the p53 tumor suppressor gene, associated with poor prognosis in cancers due to its gain-of-function activity.
• Mechanisms driving the accumulation of the p53^R175H oncoprotein, despite high expression, are not fully understood.

Purpose of the Study:

• To identify novel regulators of p53^R175H protein stability.
• To elucidate the functional and mechanistic roles of these regulators in p53^R175H-driven tumorigenesis.

Main Methods:

• Identification and characterization of a novel long non-coding RNA (lncRNA), LFPM.
• Investigation of LFPM's interaction with p53^R175H using biophysical methods.
• Analysis of LFPM's effect on p53^R175H degradation pathway involving E3 ubiquitin ligase RING1.
• Assessment of LFPM's role in cancer cell proliferation and ferroptosis resistance.
• Correlation analysis of LFPM expression with clinical outcomes in cancer patients.

Main Results:

• A novel lncRNA, LFPM, was identified that specifically binds to the p53^R175H mutant protein, enhancing its stability.
• LFPM transcription is repressed by wild-type p53 but not by p53^R175H, creating a positive feedback loop.
• LFPM promotes cancer cell proliferation and resistance to ferroptosis.
• LFPM inhibits p53^R175H degradation by disrupting its interaction with the E3 ubiquitin ligase RING1.
• Elevated LFPM expression is linked to worse survival in patients with p53^R175H-mutant cancers.

Conclusions:

• LFPM is a key factor in stabilizing the oncogenic p53^R175H protein, contributing to tumorigenesis.
• The LFPM-p53^R175H axis represents a potential therapeutic target for p53^R175H-mutant cancers.