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

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 efficacy, 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 histological 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‑associated 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, the restoration of PDLIM2 suppresses lung tumor growth, enhances chemosensitivity, and promotes antitumor immunity, including response to immune checkpoint inhibitors. In addition, a protumoral mechanism of PDLIM2 downregulation involves mitochondrial dysfunction and accumulation of oncometabolites that lead to the activation of hypoxia inducible factor‑1α signaling. Overall, PDLIM2 is emerging as a biomarker and therapeutic target for lung cancer management.