Collagen modifying enzyme P4HA1 is overexpressed and plays a role in lung adenocarcinoma

Robinson, Alyncia D.; Chakravarthi, Balabhadrapatruni V. S. K.; Agarwal, Sumit; Chandrashekar, Darshan S.; Davenport, Mackenzie L.; Chen, Guoan; Manne, Upender; Beer, David G.; Edmonds, Mick D.; Varambally, Sooryanarayana

doi:10.1016/j.tranon.2021.101128

Cited by 15 publications

(14 citation statements)

References 36 publications

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“…Zhou et al reported that P4HA1 overexpression was linked to poor survival and immune infiltrates in LUAD ( Zhou et al, 2020 ). Robinson AD et al revealed that P4HA1 was required for lung cancer cell growth and invasion, suggesting its potential as a valid therapeutic target in lung adenocarcinoma ( Robinson et al, 2021 ). Additionally, our study focused on P4HA1 impact on lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

P4HA1, a Prognostic Biomarker that Correlates With Immune Infiltrates in Lung Adenocarcinoma and Pan-Cancer

Zhao

Liu

2021

Front. Cell Dev. Biol.

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Objective: Prolyl 4-hydroxylase, alpha polypeptide I (P4HA1), a key enzyme in collagen synthesis, comprises two identical alpha subunits and two beta subunits. However, the immunomodulatory role of P4HA1 in tumor immune microenvironment (TIME) remains unclear. This study aimed to evaluate the prognostic value of P4HA1 in pan-cancer and explore the relationship between P4HA1 expression and TIME.Methods: P4HA1 expression, clinical features, mutations, DNA methylation, copy number alteration, and prognostic value in pan-cancer were investigated using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression data. Pathway enrichment analysis of P4HA1 was performed using R package “clusterProfiler.” The correlation between immune cell infiltration level and P4HA1 expression was analyzed using three sources of immune cell infiltration data, including ImmuCellAI database, TIMER2 database, and a published work.Results: P4HA1 was substantially overexpressed in most cancer types. P4HA1 overexpression was associated with poor survival in patients. Additionally, we discovered that P4HA1 expression was positively associated with infiltration levels of immunosuppressive cells, such as tumor-associated macrophages, cancer-associated fibroblasts, nTregs, and iTregs, and negatively correlated with CD8+ T and NK cells in pan-cancer.Conclusions: Our results highlighted that P4HA1 might serve as a potential prognostic biomarker in pan-cancer. P4HA1 overexpression is indicative of an immunosuppressive microenvironment. P4HA1 may be a potential target of immunotherapy.

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Section: Discussionmentioning

confidence: 99%

P4HA1, a Prognostic Biomarker that Correlates With Immune Infiltrates in Lung Adenocarcinoma and Pan-Cancer

Zhao

Liu

2021

Front. Cell Dev. Biol.

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“…In breast cancer, P4HA1 can regulate HIF-1α expression via regulating αketoglutarate (α-KG) and succinate levels [23], so as to promote chemoresistance by regulating HIF- show that knockdown of P4HA1 can impaire the invasion of LN18 and T98G cells by regulating the expression pattern of EMT-related genes [11]. In LUAD, P4HA1 is required for cancer cell growth and invasion [10].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, P4HA1 is essential for lung adenocarcinoma (LUAD) cell growth and invasion and may be a valid therapeutic target in LUAD [10]. Hypoxia can promote the metastasis of glioblastoma multiforme (GBM) via the L-Arg/P4HA1 axis, and increased P4HA1 level is associated with poor prognosis with advanced histological grade [11].…”

Section: Introductionmentioning

confidence: 99%

P4HA1 Acts as a Potential Target in Renal Cell Carcinoma and Pan-cancer

Li¹,

Ge²,

Qian³

et al. 2021

Preprint

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Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) plays a vital role in providing the major part of the catalytic site of the active enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors, nevertheless, the pan-analysis of P4HA1 remains unspecified. Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 across the datasets of The Cancer Genome Atlas (TCGA ) and Kaplan-Meier Plotter. The genomic and epigenetic alterations, correlation with immune infiltration and DNA methylation of P4HA1 in different cancers were also analyzed across multiple databases. Moreover, we further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC). Results: The results characterized the different expression profile and prognostic values of P4HA1 in pan-cancer. Remarkably, P4HA1 expression was increased in kidney renal clear cell carcinoma (KIRC) and positively correlated with the OS and DFS of patients with kidney renal papillary cell carcinoma (KIRP). In addition, a positive correlation between P4HA1 expression and immune cell infiltration in KIRC was observed. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability and tumor mutation burden in kidney chromophobe (KICH). Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion and the epithelial–mesenchymal transition (EMT) of RCC cells. Conclusion: Overall, our study suggested that P4HA1 might play a significant role in tumorigenesis and have the potential to be the target for the prognosis and therapy for several malignant tumors, especially for RCC.

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“…In addition, we also identified significant upregulation of proline hydroxylation on glycolysis enzymes pyruvate kinase (PKM) and enolase (ENO1), heat-shock protein HSPA5 as well as autophagy protein Parkin (PARK7) (Figure 7D). P4HB, a member of the collagen prolyl 4-hydroxylase enzyme, also showed significant increase in proline hydroxylation (Figure 7D), likely due to increased prolyl 4-hydroxylase activity in lung cancer [22]. To reveal the functional significance of upregulated or downregulated Hyp substrates, we performed pathway and annotation enrichment analysis.…”

Section: Tissue-specific Distribution Of Hyp Proteomementioning

confidence: 99%

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

Gong

Behera

Erber

et al. 2022

Preprint

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Proline hydroxylation (Hyp) regulates protein structure, stability and protein-protein interaction and is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the proline hydroxylation proteome, we integrated various data sources for deep proteome profiling of proline hydroxylation proteome in human and developed HypDB (https://www.HypDB.site), an annotated database and web server for proline hydroxylation proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 15319 non-redundant Hyp sites and 8226 sites with high confidence on human proteins. Annotation analysis revealed significant enrichment of proline hydroxylation on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of proline hydroxylation in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize proline hydroxylation in pathways and diseases.

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Collagen modifying enzyme P4HA1 is overexpressed and plays a role in lung adenocarcinoma

Cited by 15 publications

References 36 publications

P4HA1, a Prognostic Biomarker that Correlates With Immune Infiltrates in Lung Adenocarcinoma and Pan-Cancer

P4HA1, a Prognostic Biomarker that Correlates With Immune Infiltrates in Lung Adenocarcinoma and Pan-Cancer

P4HA1 Acts as a Potential Target in Renal Cell Carcinoma and Pan-cancer

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

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