PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression - Review

Sep 22, 2026

Lung cancer remains a leading cause of cancer-related mortality worldwide, driving the search for new targets to strengthen early detection, treatment efficacy, and long-term patient outcomes. PDZ and LIM domain protein 2 (PDLIM2) is a multifunctional adaptor implicated in lung cancer biology. Despite context-dependent roles across cancers, clinical, genetic, and experimental data consistently indicate that PDLIM2 acts as a tumor suppressor, with its loss linked to poor prognosis. Mechanistically, it restrains NF-κB/RelA and STAT3-driven inflammation, proliferation, survival, immune evasion, and metabolic reprogramming, and is downregulated via coordinated genetic and epigenetic mechanisms, offering biomarker and therapeutic potential.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Contents

Introduction

PDLIM protein family and structural features of PDLIM2

The role of PDLIM2 in ubiquitination

Tumor-suppressive and oncogenic roles of PDLIM2 in human cancers

Downregulation of PDLIM2 in lung cancer and its clinical implications

Mechanisms underlying PDLIM2 suppression in lung cancer

Mechanisms of PDLIM2-mediated tumor suppression in lung cancer

Future directions and challenges in PDLIM2-targeted therapy

Conclusion

INTERNATIONAL JOURNAL OF ONCOLOGY 69: 96, 2026 PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review) TSUNG‑HSIEN CHUANG 1* , JENG‑HUNG GUO2* , JING‑XING YANG3 , JEN‑CHIH TSENG4 , HUNG‑JUNG WANG5 and CHAO‑YANG LAI6 1Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970473, Taiwan, R.O.C. ; 2Department of Neurosurgery, China Medical University Hospital, Taichung 404327, Taiwan, R.O.C. ; 3 Jim and Eleanor Randall Department of Surgery, Cedars‑Sinai Medical Center, Los Angeles, CA 90048, USA; 4 Immunology Research Center, National Health Research Institutes, Miaoli 350401, Taiwan, R.O.C.; 5 Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan, R.O.C.; 6 Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan, R.O.C. Received April 8, 2026; Accepted June 22, 2026 DOI: 10.3892/ijo.2026.5909 Abstract. Lung cancer is a leading cause of cancer‑related mortality worldwide, which underscores the need to identify novel targets for improving early detection, therapeutic effi‑ cacy, and long‑term patient outcomes. PDZ and LIM domain protein 2 (PDLIM2) is a multifunctional adaptor protein that plays a role in cancer biology, particularly in lung cancer. Although PDLIM2 exerts divergent functions across various cancer types, substantial clinical, genetic, and experimental evidence consistently supports its role as a tumor suppressor in lung cancer. PDLIM2 expression is markedly downregulated in the majority of lung tumors representing various histo‑ logical subtypes and disease stages, and its loss is strongly associated with poor prognosis. Mechanistically, it functions as an E3 ubiquitin ligase or ubiquitin ligase enhancer to promote the degradation of key transcription factors, including NF‑κB/RelA and STAT3, thereby restraining tumor‑associ‑ ated inflammation, proliferation, survival, immune evasion, and metabolic reprogramming. PDLIM2 downregulation in lung cancer occurs through coordinated genetic and epigenetic mechanisms, including loss of heterozygosity at chromosome 8p21, promoter hypermethylation, histone deacetylation, and oxidative stress‑driven transcriptional repression. Functionally, Correspondence to: Dr Chao‑Yang Lai, Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng, Taichung 41354, Taiwan, R.O.C. E‑mail: [chaoyang@asia.edu.tw](chaoyang@asia.edu.tw) *Contributed equally Key words: immunoregulation, lung cancer, mitochondrial metabolism, PDZ and LIM domain protein 2, tumor suppression, ubiquitination the restoration of PDLIM2 suppresses lung tumor growth, enhances chemosensitivity, and promotes antitumor immu‑ nity, including response to immune checkpoint inhibitors. In addition, a protumoral mechanism of PDLIM2 downregula‑ tion involves mitochondrial dysfunction and accumulation of oncometabolites that lead to the activation of hypoxia induc‑ ible factor‑1α signaling. Overall, PDLIM2 is emerging as abiomarker and therapeutic target for lung cancer management. Contents 1. Introduction 2. PDLIM protein family and structural features of PDLIM2 3. The role of PDLIM2 in ubiquitination 4. Tumor‑suppressive and oncogenic roles of PDLIM2 inhuman cancers 5. Downregulation of PDLIM2 in lung cancer and its clinical implications 6. Mechanisms underlying PDLIM2 suppression in lung cancer 7. Mechanisms of PDLIM2‑mediated tumor suppression in lung cancer 8. Future directions and challenges in PDLIM2‑targeted therapy 9. Conclusion 1. Introduction Lung cancer is one of the most devastating malignancies worldwide, exerting a profound effect on patients, fami‑ lies, healthcare systems, and society. Lung cancer is often diagnosed at an advanced stage, when symptoms, such as persistent cough, dyspnea, wei

FAQs

What role does PDLIM2 play in lung cancer suppression?

PDLIM2 functions as a tumor suppressor in lung cancer. It promotes degradation of key transcription factors such as NF-κB/RelA and STAT3, thereby restraining tumor-associated inflammation, proliferation, survival, immune evasion, and metabolic reprogramming.

How is PDLIM2 expression downregulated in lung cancer?

PDLIM2 downregulation involves coordinated genetic and epigenetic mechanisms, including loss of heterozygosity at chromosome 8p21, promoter hypermethylation, histone deacetylation, and oxidative stress-driven transcriptional repression.

What therapeutic or biomarker potential is associated with PDLIM2?

Restoring PDLIM2 suppresses lung tumor growth, enhances chemosensitivity, and promotes antitumor immunity, including response to immune checkpoint inhibitors. The review also describes PDLIM2 as an emerging biomarker and therapeutic target for lung cancer management.

Sep 22, 2026

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