2. Academic Validation
  3. PDZRN4 suppresses lung adenocarcinoma progression via inhibiting ubiquitin-mediated HIF-1A degradation

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

  • Oncogene. 2025 Dec 29. doi: 10.1038/s41388-025-03670-z.
Honghao Li # 1 2,  Junfeng Wu # 1 2,  Hua Dai # 3,  Jiaming Li 4,  Xiaoyan Bai 1,  Yueli Sun 1,  Jiaxin Lin 1,  Yangsi Li 1,  Peng Li 5,  Lingchao Shi 5,  Zhen Wang 1,  Haiyan Tu 1,  Ee Ke 6
Affiliations

Affiliations

  • 1 Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 2 The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 3 Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
  • 4 Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China.
  • 5 Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 6 Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41461926 DOI: 10.1038/s41388-025-03670-z
Abstract

Indolent lung Cancer is characterized by slow progression, and the patient may die of Other causes before it becomes symptomatic. The increasing usage of lung Cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung Cancer patients. In this study, we performed high-throughput whole-exome Sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4, rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote Apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung Cancer cell growth in vitro and in vivo. With the EGFRL858R-driven lung Cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung Cancer and to avoid overdiagnosis. Graphical Abstract: Germline variation rs74955204 (p.G121E, c.362 G > A) in PDZRN4 significantly upregulated PDZRN4 expression and resulted in indolent growth of LUAD. Overexpressed PDZRN4 inhibits the ubiquitylation of HIF-1A by TRIM28, activating HIF-1A-IGFBP3 signaling to promote Apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, thus restricting lung Cancer cell growth.

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