PDZRN4 suppresses lung adenocarcinoma progression via inhibiting ubiquitin-mediated HIF-1A degradation.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Indolent lung cancer progresses slowly, often detected incidentally through screening.
• Increased lung cancer screening leads to overdiagnosis and overtreatment of indolent cases.
• Distinguishing indolent from aggressive lung adenocarcinoma (LUAD) is crucial for appropriate management.

Purpose of the Study:

• To identify genetic factors associated with indolent LUAD.
• To investigate the therapeutic potential of PDZRN4 in LUAD.
• To explore PDZRN4 as a biomarker for early detection of indolent LUAD.

Main Methods:

• High-throughput whole-exome sequencing of LUAD patients (indolent vs. aggressive).
• Analysis of germline variation rs74955204 in PDZRN4.
• In vitro and in vivo experiments using LUAD cell lines and mouse models.
• Investigation of PDZRN4's effect on HIF-1A ubiquitylation, apoptosis, and EGFR-AKT signaling.

Main Results:

• A novel germline variant, rs74955204 (p.G121E), in PDZRN4 was identified in indolent LUAD patients.
• This variant upregulates PDZRN4 expression, correlating positively with LUAD patient survival.
• PDZRN4 overexpression inhibits HIF-1A ubiquitylation, activates HIF-1A-IGFBP3 signaling (promoting apoptosis), and induces NDRG1 to inhibit EGFR-AKT signaling, restricting LUAD growth.
• PDZRN4 knockout accelerated LUAD growth, while overexpression suppressed it in vivo.
• Recombinant PDZRN4 and retinoic acid inhibited EGFR-driven LUAD growth and overcame osimertinib resistance.

Conclusions:

• Targeting PDZRN4 represents a potential therapeutic strategy for LUAD.
• The PDZRN4 rs74955204 variant may serve as a biomarker for early detection of indolent LUAD, aiding in the avoidance of overdiagnosis.