PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

German, Natalie J.; Yoon, Haejin; Yusuf, Rushdia Z.; Murphy, John P.; Finley, Lydia W.S.; Laurent, Gaëlle; Haas, Wilhelm; Satterstrom, F. Kyle; Guarnerio, Jlenia; Zaganjor, Elma; Santos, Daniel; Pandolfi, Pier Paolo; Beck, Andrew H.; Gygi, Steven P.; Scadden, David T.; Kaelin, William G.; Haigis, Marcia C.

doi:10.1016/j.molcel.2016.08.014

Cited by 131 publications

(131 citation statements)

References 55 publications

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“…PHDs, a family of hypoxia-induced hydroxylases (39), activate the cell proliferative signaling (40), participate in cancer metabolism (41), and regulate the development of regulatory T cells (42) through downstream target proteins, including hypoxia-inducible factor 1a (43), epidermal growth factor receptor (40), TNF-a (44), and IKK (45). As an important intermediate product in tricarboxylic acid cycles, AKG acts not only as the ligand for GPR99 receptor but also as a sensor of PHDs.…”

Section: Discussionmentioning

confidence: 99%

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

et al. 2017

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Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the β adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.-Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway.

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Section: Discussionmentioning

confidence: 99%

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

et al. 2017

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“…Hydoxylation of FOXO3a by EGLN2 destabilized FOXO3a by preventing its interaction with the USP9x deubiquitinase (Zheng et al, 2014). EGLN3-mediated hydroxylation of Acetyl-CoA Carboxylase (ACC2) leads to decreased fatty acid oxidation under normoxia and high nutrient availability (German et al, 2016). Pyruvate kinase M2, the proliferogenic splice form of pyruvate kinase, appears to be another major metabolic enzyme serving as hydroxylation substrate.…”

Section: Egln-hif Beyond Conventional Hypoxic Responsesmentioning

confidence: 99%

The EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks

2017

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SUMMARY The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications.

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“…Cancer cells can amplify fatty acid catabolism through PHD3 repression to promote survival by serving as a source of ATP or NADPH, in preference over glucose and glutamine utilization. While the details of this discovery have recently been published in a peer-review companion paper [18], the patent application focuses on novel personalized cancer treatment strategies. For PHD3-underexpressing cancers, this can be achieved by inhibitors of fatty acid oxidation.…”

Section: Wo/2016/164295mentioning

confidence: 99%

Patent Highlights October–November 2016

Mucke¹

2017

Pharm. Pat. Anal.

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MeSH keywords: alcohol oxidoreductases • allergy and immunology • chemotactic factors • eicosanoid receptorsMetabolism of arachidonic acid by the 5-lipoxygenase pathway leads to the formation of leukotrienes including 5(S)-hydroxyeicosatetraenoic acid (5-HETE), which is oxidized by 5-hydroxyeicosanoid dehydrogenase to give 5-oxo-ETE (OXE), a potent chemoattractant primarily for eosinophils and also for neutrophils. The OXE receptor [1] is also expressed on monocytes, as well as on prostate tumor cells; antagonists might be useful as therapeutic or prophylactic agents for asthma [2], allergic rhinitis, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis and certain cancers [3]. The inventors, who have published extensively on the subject, had reported 5-(6-chloro-2-hexyl-1H-indol-1-yl)-5-oxo-valeric acid as an OXE antagonist lead compound with an IC 50 of 400 nM [4]. Further refinements using a structure-based approach in which substituents mimicking the essential polar (C1-C5) and hydrophobic (C15-C20) regions of OXE were incorporated in an indole scaffold, had identified racemic compounds with IC 50 values below 30 nM, widely disparate between the stereoisomers [5]. In the present patent application, the limits have been pushed much further: (S)-5-(5-chloro-2-(6-(3-chlorophenyl)hexyl)-1-methyl-1H-indol-3-yl)-3-methyl-5-oxopentanoic acid has an IC 50 of 8 pM. When administered to cynomolgus monkeys at a dose of either 5 mg/kg or 2 × 5 mg/kg 8 h apart, it was found converted to a single polar metabolite that also showed potent OXE antagonistic activity.

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PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2

Cited by 131 publications

References 55 publications

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

The EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks

Patent Highlights October–November 2016

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