The non-canonical functions of HIF prolyl hydroxylases and their dual roles in cancer

Yu, Mengchao; Lun, Jie; Zhang, Hongwei; Zhu, Lei; Zhang, Gang; Fang, Jing

doi:10.1016/j.biocel.2021.105982

Cited by 11 publications

(5 citation statements)

References 132 publications

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“…The inhibition of translation with cycloheximide (CHX) showed that HA‐tagged ORMDL3 (HA‐ORMDL3) half‐life was 1.7 h (Fig 3A), indicating a relatively fast turnover, similar to the one observed in yeast (Schmidt et al , 2019). To identify the regulatory mechanisms controlling ORMDLs levels, we analyzed ORMDLs sequence properties and observed the presence in the C‐terminus of a degenerate prolyl hydroxylase (PHD) consensus sequence, known to regulate the levels of hypoxia‐inducible factor 1α (HIF‐1α) (Jaakkola et al , 2001) and other proteins (Guo et al , 2016; Yu et al , 2021) via ubiquitination (Fig 3B). Interestingly, the inhibition of PHD activity with the hydroxylase inhibitor dimethyloxalylglycine (DMOG) elevated ORMDLs to the same extent as S1P, suggesting that PHD‐mediated ubiquitination controlled the abundance of ORMDLs (Fig 3C).…”

Section: Resultsmentioning

confidence: 99%

Sphingosine‐1‐phosphate controls endothelial sphingolipid homeostasis via ORMDL

et al. 2022

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Disruption of sphingolipid homeostasis and signaling has been implicated in diabetes, cancer, cardiometabolic, and neurodegenerative disorders. Yet, mechanisms governing cellular sensing and regulation of sphingolipid homeostasis remain largely unknown. In yeast, serine palmitoyltransferase, catalyzing the first and rate‐limiting step of sphingolipid de novo biosynthesis, is negatively regulated by Orm1 and 2. Lowering sphingolipids triggers Orms phosphorylation, upregulation of serine palmitoyltransferase activity and sphingolipid de novo biosynthesis. However, mammalian orthologs ORMDLs lack the N‐terminus hosting the phosphosites. Thus, which sphingolipid(s) are sensed by the cells, and mechanisms of homeostasis remain largely unknown. Here, we identify sphingosine‐1‐phosphate (S1P) as key sphingolipid sensed by cells via S1PRs to maintain homeostasis. The increase in S1P‐S1PR signaling stabilizes ORMDLs, restraining SPT activity. Mechanistically, the hydroxylation of ORMDLs at Pro137 allows a constitutive degradation of ORMDLs via ubiquitin‐proteasome pathway, preserving SPT activity. Disrupting S1PR/ORMDL axis results in ceramide accrual, mitochondrial dysfunction, impaired signal transduction, all underlying endothelial dysfunction, early event in the onset of cardio‐ and cerebrovascular diseases. Our discovery may provide the molecular basis for therapeutic intervention restoring sphingolipid homeostasis.

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Section: Resultsmentioning

confidence: 99%

Sphingosine‐1‐phosphate controls endothelial sphingolipid homeostasis via ORMDL

et al. 2022

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“…Proline hydroxylation (Hyp) is a key oxygen-sensitive posttranslational modification that is irreversible and catalyzed by proline hydroxylase with oxygen as the substrate and iron, aketoglutarate, and ascorbic acid as cofactors (80)(81)(82)(83)(84). These modifications affect the structure, activity and characteristics of protein interactions within cells and play a key role in cancer development and disease progression (84,85). Proline hydroxylase domain (PHD) protein is one of the main enzyme families regulating proline hydroxylation in cells, including three main proteins, PHD-1, PHD-2, and PHD-3 (86,87).…”

Section: Hydroxylationmentioning

confidence: 99%

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

et al. 2022

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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.

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“…All members of this enzyme family hydroxylate the conserved proline residues present in HIFs-α family members; however, they present different affinities. PHD2 appears to have a greater affinity for HIF-1α under normoxic conditions, while PHD1 and PHD3 are proposed to predominantly contribute to HIF-2α regulation [23][24][25]. The cell oxygen sensing system is altered in many tumors, which prefer glycolytic metabolism despite being in the presence of oxygen (the Warburg effect).…”

Section: Introductionmentioning

confidence: 99%

“…Again, overexpression of PHD2 inhibits liver cancer growth. On the other hand, its inhibition reduces the growth of osteosarcoma [24,25]. What determines the pro-and antitumor functions of each isoform, as well as their different substrate affinities is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations

Camagni

Minervini

Tosatto

2023

IJMS

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The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.

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The non-canonical functions of HIF prolyl hydroxylases and their dual roles in cancer

Cited by 11 publications

References 132 publications

Sphingosine‐1‐phosphate controls endothelial sphingolipid homeostasis via ORMDL

Sphingosine‐1‐phosphate controls endothelial sphingolipid homeostasis via ORMDL

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations

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