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

  • Authors:
    • Tsung-Hsien Chuang
    • Jeng-Hung Guo
    • Jing-Xing Yang
    • Jen-Chih Tseng
    • Hung-Jung Wang
    • Chao-Yang Lai
  • View Affiliations / Copyright

    Affiliations: Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970473, Taiwan, R.O.C., Department of Neurosurgery, China Medical University Hospital, Taichung 404327, Taiwan, R.O.C., Jim and Eleanor Randall Department of Surgery, Cedars‑Sinai Medical Center, Los Angeles, CA 90048, USA, Immunology Research Center, National Health Research Institutes, Miaoli 350401, Taiwan, R.O.C., Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan, R.O.C., Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan, R.O.C.
    Copyright: © Chuang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 96
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    Published online on: July 3, 2026
       https://doi.org/10.3892/ijo.2026.5909
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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.
View Figures

Figure 1

Protein structures of PDLIM family
members and the LIM domain of PDLIM2. (A) Protein architecture of
the PDLIM proteins. PDLIM proteins contain a PDZ domain at the
N-terminus with or without a middle ZM domain and one or three LIM
domains at the C-terminus. Of these members, PDLIM2 contains 352
amino acid (aa) residues with a PDZ domain and a LIM domain
spanning from aa 1 to 84 and aa 284 to 344, respectively. (B) The
LIM domain of PDLIM2. The protein sequence of the PDLIM2 LIM domain
is shown at the top of the panel. Cysteine and histidine residues
involved in the zinc-ion binding are highlighted in red. The
architecture of this LIM domain was predicted using the AlphaFold
program (https://alphafoldserver.com/).
Orange round dots represent zinc ions. The locations of the
cysteine- and histidine-binding residues are shown. PDLIM, PDZ and
LIM domain-containing protein; PDZ, postsynaptic density protein
95/discs large/zonula occludens-1 domain; LIM, Lin-11, Isl-1, and
Mec-3 domain; ZM, zinc-binding motif; aa, amino acid; LIM2, LIM
domain-containing protein 2.

Figure 2

Mechanisms by which PDLIM2 promotes
the ubiquitination and degradation of p65/RelA. Schematic
illustration of the distinct molecular mechanisms by which PDLIM2
promotes the ubiquitination and degradation of the p65/RelA
subunit. (A) Monomeric mechanism. PDLIM2 promotes the
polyubiquitination of p65/RelA through its monomeric activity. (B)
Heterodimeric mechanism. PDLIM2 forms functional complexes with
other ubiquitin ligases, such as MKRN2, to enhance p65/RelA
ubiquitination through cooperative E3 activity. (C) CRL
complex-dependent mechanism. PDLIM2 acts within CRL complexes to
enhance p65/RelA ubiquitination. Through stabilization of the
ligase complex, PDLIM2 promotes efficient polyubiquitination and
proteasomal degradation of p65/RelA. Taken together, these
mechanisms highlight the multifaceted roles of PDLIM2 in regulating
NF-κB signaling through proteasomal and adaptor-assisted ubiquitin
pathways. PDLIM2, PDZ and LIM domain-containing protein 2; MKRN2,
makorin ring finger protein 2; CRL, Cullin-RING ubiquitin
ligase.

Figure 3

Molecular mechanisms underlying
PDLIM2 suppression in lung cancer. PDLIM2 is downregulated in lung
cancer through coordinated genetic, epigenetic, transcriptional,
and post-transcriptional mechanisms. These mechanisms may converge
to suppress PDLIM2 expression in lung cancer. PDLIM2, PDZ and LIM
domain-containing protein 2.

Figure 4

Proposed model illustrating how
PDLIM2 downregulation promotes lung tumor progression through
interconnected ubiquitination-, immunity-, mitochondria metabolic-,
and hypoxia-associated feed-forward signaling networks. Loss of
PDLIM2 disrupts the ubiquitination-mediated degradation of NF-κB
and STAT3, resulting in persistent inflammatory and pro-survival
signaling that induces the expression of CCND1, BCL2, VEGF, MMPs,
CXCL8, and MDR1, thereby promoting proliferation, angiogenesis,
metastasis, and chemoresistance. PDLIM2 deficiency also suppresses
antitumor immunity by reducing macrophage phagocytosis, impairing
MHC-I antigen presentation and cytotoxic T-cell recognition, and
decreasing the response to PD-1/PD-L1 blockade. In parallel,
disruption of mitochondrial homeostasis through reduced SDH/TCA
cycle activity increases mtROS, succinate, and fumarate
accumulation, leading to the stabilization of HIF-1α (blue arrow
lines). Activated HIF-1α further enhances glycolytic metabolism,
oxidative stress, inflammatory signaling, and NF-κB/STAT3
activation. Increased ROS production further suppresses PDLIM2
expression through BACH1 (red arrow lines). These events establish
a self-reinforcing feed-forward loop that drives tumor growth,
metabolic adaptation, therapeutic resistance, and malignant
progression in lung cancer. PDLIM2, PDZ and LIM domain-containing
protein 2; CCND1, cyclin D1; VEGF, vascular endothelial growth
factor; CXCL8, C-X-C motif chemokine ligand 8; MDR1, multidrug
resistance protein 1; MHC-I, major histocompatibility complex class
I; PD-1, programmed cell death protein 1; PD-L1, programmed
death-ligand 1; SDH, succinate dehydrogenase; TCA, tricarboxylic
acid cycle; mtROS, mitochondrial reactive oxygen species; HIF-1α,
hypoxia-inducible factor 1 alpha; BACH1, BTB and CNC homology
1.
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Copy and paste a formatted citation
Spandidos Publications style
Chuang T, Guo J, Yang J, Tseng J, Wang H and Lai C: PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review). Int J Oncol 69: 96, 2026.
APA
Chuang, T., Guo, J., Yang, J., Tseng, J., Wang, H., & Lai, C. (2026). PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review). International Journal of Oncology, 69, 96. https://doi.org/10.3892/ijo.2026.5909
MLA
Chuang, T., Guo, J., Yang, J., Tseng, J., Wang, H., Lai, C."PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review)". International Journal of Oncology 69.2 (2026): 96.
Chicago
Chuang, T., Guo, J., Yang, J., Tseng, J., Wang, H., Lai, C."PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review)". International Journal of Oncology 69, no. 2 (2026): 96. https://doi.org/10.3892/ijo.2026.5909
Copy and paste a formatted citation
x
Spandidos Publications style
Chuang T, Guo J, Yang J, Tseng J, Wang H and Lai C: PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review). Int J Oncol 69: 96, 2026.
APA
Chuang, T., Guo, J., Yang, J., Tseng, J., Wang, H., & Lai, C. (2026). PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review). International Journal of Oncology, 69, 96. https://doi.org/10.3892/ijo.2026.5909
MLA
Chuang, T., Guo, J., Yang, J., Tseng, J., Wang, H., Lai, C."PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review)". International Journal of Oncology 69.2 (2026): 96.
Chicago
Chuang, T., Guo, J., Yang, J., Tseng, J., Wang, H., Lai, C."PDLIM2 acts as a central regulator of ubiquitination, immune signaling, and mitochondrial metabolism in lung cancer suppression (Review)". International Journal of Oncology 69, no. 2 (2026): 96. https://doi.org/10.3892/ijo.2026.5909
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