Dual prognostic role of 2‐oxoglutarate‐dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance

Chang, Wai Hoong; Forde, Dónall; Lai, Alvina G.

doi:10.1186/s40880-019-0369-5

Cited by 45 publications

(38 citation statements)

References 54 publications

(48 reference statements)

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“…Several studies have suggested that PLOD2 is correlated with poor prognosis of multiple cancers, including sarcoma, lung cancer, renal cell carcinoma, breast cancer, cervical cancer and bladder cancer [19,[27][28][29][30][31]. PLOD2 reinforces the migration capacity of cancer cells, and also promotes cancer cells migration along the "highway" linear collagen [19,28,32].…”

Section: Discussionmentioning

confidence: 99%

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Wei

et al. 2019

Cell Commun Signal

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Background: Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear. Methods: Adipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co-implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes. Results: It was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer. Conclusion: In summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Wei

et al. 2019

Cell Commun Signal

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“…Expression of PLOD genes was observed to be elevated in clear cell renal cell carcinoma (ccRCC) when compared with normal kidney tissues, and genetic mutations of PLOD genes were presented in ~3% ccRCC tissues. Furthermore, they found that mRNA of PLOD genes was positively associated with the prognosis of ccRCC patients, while the expression pattern of PLOD genes in gastric cancer was different from those in ccRCC [ 14 ]. The expression of the PLOD family was also increased in gastric cancer compared with normal tissues.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study assessed the expression and prognostic value of PLOD1/2/3 in wild-type and genetically mutated clear cell renal cell carcinoma (ccRCC) patients. Compared with the paired normal kidney tissues, ccRCC tissues expressed notably high PLOD1/2/3 mRNA and protein [ 14 ]. Here, high-level PLOD1/2/3 expression was strongly linked to advanced pathological tumor stage and overall survival.…”

Section: Introductionmentioning

confidence: 99%

PLOD1 Is a Prognostic Biomarker and Mediator of Proliferation and Invasion in Osteosarcoma

Jiang

Guo

Yuan

et al. 2020

BioMed Research International

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Objective. Osteosarcoma is the most common primary bone tumor and most frequently develops during adolescence. PLOD family was mainly involved in lysyl hydroxylation and rarely investigated in cancers, especially in osteosarcoma. The aim of this study was to investigate the expression pattern and oncogenic role of PLODs in osteosarcoma. Methods. GEO datasets (GSE16088, GSE33382, and GSE16091) and validation cohort were used to analyze the expression pattern of PLODs in osteosarcoma. Kaplan-Meier survival analysis was used to explore the prognostic role of PLODs in patients with osteosarcoma. RNA interference of KRT19 was performed using small interfering RNA (siRNA) in MG-63 and U-2OS cells. The proliferation was detected using CCK8, clone formation assay, and EdU staining. Migration and invasion were determined using the transwell assay. Western blots and luciferase assays for β-catenin-T-cell factor protein/β-catenin-lymphoid enhancer factor- (β-catenin-TCF/LEF-) driven transcriptional activity. Results. PLOD1 was upregulated in osteosarcoma tissues compared with control tissues both in public datasets and in in-house cohort. The expression of PLOD1 in osteosarcoma tissues was significantly associated with the status of distance metastasis and Enneking stage, while PLOD2 and PLOD3 expressed no difference between osteosarcoma and benign tissues and showed no correlation with tumor malignancy. Furthermore, Kaplan-Meier survival analysis revealed that patients with a higher level of PLOD1 had worse prognosis than those with a lower level of PLOD1. Downregulation of PLOD1 dramatically inhibited proliferation, migration, and invasion of MG-63 cells and U-2OS cells in vitro. Mechanistically, PLOD1 regulated β-catenin signaling pathway in osteosarcoma. Conclusion. Our results indicated that PLOD1 promoted proliferation, migration, and invasion of osteosarcoma cells. PLOD1 was a novel prognostic marker, as well as a therapeutic target in osteosarcoma.

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“…In support of a pro-oncogenic role in cancer, high JMJD5 expression has been correlated with increased metastasis, invasiveness and poor survival in breast, colorectal, prostate, and oral cancers [112][113][114][115]. Conversely, a multi-cohort retrospective study across ten cancer types has suggested that JMJD5 may function as a tumour suppressor; high expression levels were associated with a lower risk of death in pancreatic and liver cancer cohorts, while low JMJD5 levels correlated with poorer survival outcomes [116]. In fact, JMJD5 was originally identified in a tumour suppressor gene screen [93].…”

Section: Og-oxygenases: Disease Mediatorsmentioning

confidence: 99%

Human 2-oxoglutarate-dependent oxygenases: nutrient sensors, stress responders, and disease mediators

Fletcher

Coleman

2020

Biochemical Society Transactions

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Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases are a conserved enzyme class that catalyse diverse oxidative reactions across nature. In humans, these enzymes hydroxylate a broad range of biological substrates including DNA, RNA, proteins and some metabolic intermediates. Correspondingly, members of the 2OG-dependent oxygenase superfamily have been linked to fundamental biological processes, and found dysregulated in numerous human diseases. Such findings have stimulated efforts to understand both the biochemical activities and cellular functions of these enzymes, as many have been poorly studied. In this review, we focus on human 2OG-dependent oxygenases catalysing the hydroxylation of protein and polynucleotide substrates. We discuss their modulation by changes in the cellular microenvironment, particularly with respect to oxygen, iron, 2OG and the effects of oncometabolites. We also describe emerging evidence that these enzymes are responsive to cellular stresses including hypoxia and DNA damage. Moreover, we examine how dysregulation of 2OG-dependent oxygenases is associated with human disease, and the apparent paradoxical role for some of these enzymes during cancer development. Finally, we discuss some of the challenges associated with assigning biochemical activities and cellular functions to 2OG-dependent oxygenases.

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Dual prognostic role of 2‐oxoglutarate‐dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance

Cited by 45 publications

References 54 publications

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

PLOD1 Is a Prognostic Biomarker and Mediator of Proliferation and Invasion in Osteosarcoma

Human 2-oxoglutarate-dependent oxygenases: nutrient sensors, stress responders, and disease mediators

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