Comprehensive analysis of PLOD family members in low-grade gliomas using bioinformatics methods

Zhao, Yonghui; Zhang, Xiang; Yao, Junchao

doi:10.1371/journal.pone.0246097

Cited by 4 publications

(4 citation statements)

References 43 publications

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“…Lysine hydroxylase (LH) is encoded by three lysine hydroxylase genes (procollagen-lysine, 2-oxoglutarate 5-dioxygenase PLOD1 , PLOD2 , and PLOD3 ) and is a key enzyme that mediates collagen association. PLOD family genes belong to the 2-ketoglutarate-dependent dioxygenase family ( Zhao et al, 2021 ). They form homodimers in the presence of Fe 2+ and 2-ketoglutaric acid (2-OG) to hydroxylate single-chain procollagen lysines.…”

Section: Discussionmentioning

confidence: 99%

Clinical Prognostic Value of the PLOD Gene Family in Lung Adenocarcinoma

Meng

Sun

Zhang

et al. 2022

Front. Mol. Biosci.

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Accumulating evidence has implicated members of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) gene family, PLOD1, PLOD2, and PLOD3, in cancer progression and metastasis. However, their expression, prognostic value, and mechanisms underlying their roles in lung adenocarcinoma (LUAD) have not yet been reported. We downloaded PLOD data for LUAD and normal tissues from The Cancer Genome Atlas (TCGA). PLOD1-3 protein expression was evaluated using the Clinical Proteomics Tumor Analysis Consortium and Human Protein Atlas. Survival analysis was performed using the Kaplan–Meier method. A protein–protein interaction network was constructed using STRING software. The “ClusterProfiler” package was used for functional-enrichment analysis. The relationship between PLOD mRNA expression and immune infiltration was analyzed using the Tumor Immunity Assessment Resource and Tumor Immune System Interaction Database. The expression of PLODs in LUAD tissues was significantly upregulated compared with that in adjacent normal tissues. PLOD mRNA overexpression is associated with lymph node metastasis and high TNM staging. Receiver operating characteristic curve analysis showed that when the cut-off level was 6.073, the accuracy, sensitivity, and specificity of PLOD1 in distinguishing LUAD from adjacent controls were 84.4, 79.7, and 82.6%, respectively. The accuracy, sensitivity, and specificity of PLOD2 in distinguishing LUAD from adjacent controls were 81.0, 98.3, and 68.0%, respectively, at a cut-off value of 4.360. The accuracy, sensitivity, and specificity of PLOD3 in distinguishing LUAD from adjacent controls were 69.0, 86.4, and 52.0%, respectively, with a cut-off value of 5.499. Kaplan–Meier survival analysis demonstrated that LUAD patients with high PLODs had a worse prognosis than those with low PLODs. Correlation analysis showed that PLOD mRNA expression was related to immune infiltration and tumor purity. Upregulation of PLOD expression was significantly associated with poor survival and immune cell infiltration in LUAD. Our research shows that PLOD family members have potential as novel biomarkers for poor prognosis and as potential immunotherapy targets for LUAD.

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Section: Discussionmentioning

confidence: 99%

Clinical Prognostic Value of the PLOD Gene Family in Lung Adenocarcinoma

Meng

Sun

Zhang

et al. 2022

Front. Mol. Biosci.

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“…Recent studies have shown that tumor purity is linked to prognosis, mutation burden, and a robust immunological phenotype. , Our results indicate that LYN, MMP9, PSMB9, and TIMP1 were linked with the GBM microenvironment. Zhao et al demonstrated a high expression of the PLOD family with negative tumor purity and high immune infiltration . In our study, LYN was downregulated in the hypoxic condition in GBM.…”

Section: Discussionmentioning

confidence: 99%

“…Zhao et al demonstrated a high expression of the PLOD family with negative tumor purity and high immune infiltration. 89 In our study, LYN was downregulated in the hypoxic condition in GBM. According to a study by Dai and Siemann, hypoxia has little to no impact on the expression of phosphorylated LYN.…”

Section: Discussionmentioning

confidence: 99%

Design and Computational Analysis of an MMP9 Inhibitor in Hypoxia-Induced Glioblastoma Multiforme

Kumari

Kumar

2023

ACS Omega

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The main therapeutic difficulties in treating hypoxia-induced glioblastoma multiforme (GBM) are toxicity of current treatments and the resistance brought on by the microenvironment. More effective therapeutic alternatives are urgently needed to reduce tumor lethality. Hence, we screened plant-based natural product panels intending to identify novel drugs without elevating drug resistance. We explored GEO for the hypoxia GBM model and compared hypoxic genes to non-neoplastic brain cells. A total of 2429 differentially expressed genes expressed exclusively in hypoxia were identified. The functional enrichment analysis demonstrated genes associated with GBM, further PPI network was constructed, and biological pathways associated with them were explored. Seven webtools, including GEPIA2.0, TIMER2.0, TCGA-GBM, and GlioVis, were used to validate 32 hub genes discovered using Cytoscape tool in GBM patient samples. Four GBM-specific hypoxic hub genes, LYN, MMP9, PSMB9, and TIMP1, were connected to the tumor microenvironment using TIMER analysis. 11 promising hits demonstrated positive drug-likeness with nontoxic characteristics and successfully crossed blood−brain barrier and ADMET analyses. Top-ranking hits have stable intermolecular interactions with the MMP9 protein according to molecular docking, MD simulation, MM-PBSA, PCA, and DCCM analyses. Herein, we have reported flavonoids, 7,4′-dihydroxyflavan, (3R)-3-(4-hydroxybenzyl)-6-hydroxy-8-methoxy-3,4-dihydro-2H-1-benzopyran, and 4′-hydroxy-7methoxyflavan, to inhibit MMP9, a novel hypoxia gene signature that could serve as a promising predictor in various clinical applications, including GBM diagnosis, prognosis, and targeted therapy.

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“…In agreement with the observations on PLOD2 , also PLOD3 knockdown suppressed the malignant phenotype in renal cell carcinoma ( Xie et al, 2020 ). Furthermore, the entire LH/PLOD family was found correlated with metastatization of solid tumors as hepatocellular and renal cell carcinomas ( Xu et al, 2019 ; Yang et al, 2020 ), gliomas ( Zhao et al, 2021 ), gastric ( Li et al, 2020 ), and ovarian ( Guo T. et al, 2021 ) cancers. Taken together, these observations strongly point these enzymes as a hot topic in cancer research: LH/PLODs are not only widely recognized prognostic markers of cancer metastatization with poor outcome, but also very promising druggable targets for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

A Fe2+-dependent self-inhibited state influences the druggability of human collagen lysyl hydroxylase (LH/PLOD) enzymes

Scietti

Moroni²,

Mattoteia

et al. 2022

Front. Mol. Biosci.

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Multifunctional human collagen lysyl hydroxylase (LH/PLOD) enzymes catalyze post-translational hydroxylation and subsequent glycosylation of collagens, enabling their maturation and supramolecular organization in the extracellular matrix (ECM). Recently, the overexpression of LH/PLODs in the tumor microenvironment results in abnormal accumulation of these collagen post-translational modifications, which has been correlated with increased metastatic progression of a wide variety of solid tumors. These observations make LH/PLODs excellent candidates for prospective treatment of aggressive cancers. The recent years have witnessed significant research efforts to facilitate drug discovery on LH/PLODs, including molecular structure characterizations and development of reliable high-throughput enzymatic assays. Using a combination of biochemistry and in silico studies, we characterized the dual role of Fe2+ as simultaneous cofactor and inhibitor of lysyl hydroxylase activity and studied the effect of a promiscuous Fe2+ chelating agent, 2,2’-bipyridil, broadly considered a lysyl hydroxylase inhibitor. We found that at low concentrations, 2,2’-bipyridil unexpectedly enhances the LH enzymatic activity by reducing the inhibitory effect of excess Fe2+. Together, our results show a fine balance between Fe2+-dependent enzymatic activity and Fe2+-induced self-inhibited states, highlighting exquisite differences between LH/PLODs and related Fe2+, 2-oxoglutarate dioxygenases and suggesting that conventional structure-based approaches may not be suited for successful inhibitor development. These insights address outstanding questions regarding druggability of LH/PLOD lysyl hydroxylase catalytic site and provide a solid ground for upcoming drug discovery and screening campaigns.

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Comprehensive analysis of PLOD family members in low-grade gliomas using bioinformatics methods

Cited by 4 publications

References 43 publications

Clinical Prognostic Value of the PLOD Gene Family in Lung Adenocarcinoma

Clinical Prognostic Value of the PLOD Gene Family in Lung Adenocarcinoma

Design and Computational Analysis of an MMP9 Inhibitor in Hypoxia-Induced Glioblastoma Multiforme

A Fe2+-dependent self-inhibited state influences the druggability of human collagen lysyl hydroxylase (LH/PLOD) enzymes

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