Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance

Xiong, Gaofeng; Stewart, Rachel L.; Chen, Jie; Gao, Tianyan; Scott, Terrance M.; Samayoa, Luis; O’Connor, Kathleen L.; Lane, Andrew N.; Xu, Ren

doi:10.1038/s41467-018-06893-9

Cited by 188 publications

(152 citation statements)

References 68 publications

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“…They also show that overexpression P4HA1 in cancer cells induces LDHA mRNA levels, and P4HA1 expression correlates with LDHA mRNA levels in human breast cancer tissue [59] , which are consistent with our findings that highest LDHA mRNA abundance is observed…”

Section: Discussionsupporting

confidence: 92%

Persistent cell proliferation signals correlates with increased glycolysis in tumor hypoxia microenvironment across cancer types

Wei

Huang

et al. 2020

Preprint

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Background：Altered metabolism is a hallmark of cancer and glycolysis is one of the important factors promoting tumor development. Given that the absence of multi-sample big data research about glycolysis, the molecular mechanisms involved in glycolysis or the relationships between glycolysis and tumor microenvironment are not fully studied. Thus, a more comprehensive approach in a pan-cancer landscape may be needed.Methods: Here, we develop a computational pipeline to study multi-omics molecular features defining glycolysis activity and identify molecular alterations that correlate with glycolysis.We apply a 22-gene expression signature to define the glycolysis activity landscape and verify the robustness using clinically defined glycolysis samples from several previous studies. Based on gene expression signature, we classify about 5552 of 9229 tumor samples into glycolysis score-high and score-low groups across 25 cancer types from The Cancer Genome Atlas (TCGA) and demonstrate their prognostic associations. Moreover, using genomes and transcriptome data, we characterize the association of copy-number aberrations (CNAs), somatic single-nucleotide variants (SNVs) and hypoxia signature with glycolysis activity.Findings: Gene set variation analysis (GSVA) score by gene set expression was verified robustly to represent glycolytic activity and highly glycolytic tumors presented a poor overall survival in some cancer types. Then, we identified various types of molecular features promoting tumor cell proliferation were associated with glycolysis activity. Our study showed that TCA cycle and respiration electron transport were active in glycolysis-high tumors, indicating glycolysis was not a symptom of impaired oxidative metabolism. The glycolytic score significantly correlated with hypoxia score across all 3 cancer types. Glycolysis score was also associated with elevated genomic instability. In all tumor types, high glycolysis tumors exhibited characteristic driver genes altered by CNAs identified multiple oncogenes and tumor suppressors. We observed widespread glycolysis-associated dysregulation of mRNA across cancers and screened out HSPA8 and P4HA1 as the potential modulating factor to glycolysis. Besides, the expression of genes encoding glycolytic enzymes positively correlated with genes in cell cycle.Interpretation: This is the first study to identify gene expression signatures that reflect glycolysis activity, which can be easily applied to large numbers of patient samples. Our analysis establishes a computational framework for characterizing glycolysis activity using gene expression data and defines correlation of glycolysis with the hypoxia microenvironment, tumor cell cycle and proliferation at a pan-cancer landscape. The findings suggest that the mechanisms whereby hypoxia influence glycolysis are likely multifactorial.Our finding is significant not just in demonstrating definition value for glycolysis but also in providing a comprehensive molecular-level understanding of glycolysis and suggesting a framewo...

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Section: Discussionsupporting

confidence: 92%

Persistent cell proliferation signals correlates with increased glycolysis in tumor hypoxia microenvironment across cancer types

Wei

Huang

et al. 2020

Preprint

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“…High P4HA expression increases intratumoral collagen deposition (Xiong et al, 2014). It is also strongly correlated with resistance to chemotherapy and reduced survival in triple-negative breast cancer patients (Xiong et al, 2018). happens in the Golgi apparatus, where the core protein is translocated.…”

Section: Collagensmentioning

confidence: 99%

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Henke

Nandigama

Ergün

2020

Front. Mol. Biosci.

721

613

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Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

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“…Further, other hypoxia‐independent drivers, such as the oncogenic BRAFV600E mutation, have been found to increase HIF‐1α protein (the oxygen‐regulated subunit of HIF‐1) and the expression of HIF‐1‐regulated genes in melanoma (reviewed in Meierjohann, ). Recently, P4HA1 has also been found to stabilize HIF‐1α independently of oxygen levels (Xiong et al , ), leading to a positive feedback loop and increased expression of HIF‐1‐induced genes. These results suggest an important role for P4HA1 in HIF‐1 signaling pathway and the potential of P4HA1 as a prognostic marker.…”

Section: Discussionmentioning

confidence: 99%

“…DKK1, in turn, is a secreted inhibitor of Wnt signaling (Fedi et al , ), and its overexpression decreases the invasive capability of melanoma cells in vitro (Chen et al , ) and increases apoptosis in melanoma cells in vitro and in vivo (Mikheev et al , ). How P4HA1 may regulate the expression of these genes remains to be clarified, but one mechanism by which P4HA1 may affect gene expression is through stabilization of HIF‐1α (Xiong et al , ).…”

Section: Discussionmentioning

confidence: 99%

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

et al. 2020

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Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease‐specific survival using global gene expression profiling. Many of the identified potential markers of poor prognosis were associated with the epithelial–mesenchymal transition, extracellular matrix formation, and angiogenesis. We studied further the significance of one of the genes, prolyl 4‐hydroxylase subunit alpha 1 (P4HA1), in melanoma progression. P4HA1 depletion in melanoma cells reduced cell adhesion, invasion, and viability in vitro. In melanoma xenograft assays, we found that P4HA1 knockdown reduced melanoma tumor invasion as well as the deposition of collagens, particularly type IV collagen, in the interstitial extracellular matrix and in the basement membranes of tumor blood vessels, leading to vessel wall rupture and hemorrhages. Further, P4HA1 knockdown reduced the secretion of collagen triple helix repeat containing 1 (CTHRC1), an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo. Taken together, P4HA1 is an interesting potential prognostic marker and therapeutic target in primary melanomas, influencing many aspects of melanoma tumor progression.

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Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance

Cited by 188 publications

References 68 publications

Persistent cell proliferation signals correlates with increased glycolysis in tumor hypoxia microenvironment across cancer types

Persistent cell proliferation signals correlates with increased glycolysis in tumor hypoxia microenvironment across cancer types

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

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