Acetylation modification regulates GRP78 secretion in colon cancer cells

High glucose-regulated protein 78 (GRP78) expression contributes to the acquisition of a wide range of phenotypic cancer hallmarks, and the pleiotropic oncogenic functions of GRP78 may result from its diverse subcellular distribution. Interestingly, GRP78 has been reported to be secreted from solid tumour cells, participating in cell-cell communication in the tumour microenvironment. However, the mechanism underlying this secretion remains elusive. Here, we report that GRP78 is secreted from colon cancer cells via exosomes. Histone deacetylase (HDAC) inhibitors blocked GRP78 release by inducing its aggregation in the ER. Mechanistically, HDAC inhibitor treatment suppressed HDAC6 activity and led to increased GRP78 acetylation; acetylated GRP78 then bound to VPS34, a class III phosphoinositide-3 kinase, consequently preventing the sorting of GRP78 into multivesicular bodies (MVBs). Of note, we found that mimicking GRP78 acetylation by substituting the lysine at residue 633, one of the deacetylated sites of HDAC6, with a glutamine resulted in decreased GRP78 secretion and impaired tumour cell growth in vitro. Our study thus reveals a hitherto-unknown mechanism of GRP78 secretion and may also provide implications for the therapeutic use of HDAC inhibitors

pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner

Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel–Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance

Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.status: publishe

EglN2 associates with the NRF1‐PGC1α complex and controls mitochondrial function in breast cancer

Abstract The EglN2/PHD1 prolyl hydroxylase is an important oxygen sensor contributing to breast tumorigenesis. Emerging studies suggest that there is functional cross talk between oxygen sensing and mitochondrial function, both of which play an essential role for sustained tumor growth. However, the potential link between EglN2 and mitochondrial function remains largely undefined. Here, we show that EglN2 depletion decreases mitochondrial respiration in breast cancer under normoxia and hypoxia, which correlates with decreased mitochondrial DNA in a HIF1/2α‐independent manner. Integrative analyses of gene expression profile and genomewide binding of EglN2 under hypoxic conditions reveal nuclear respiratory factor 1 (NRF1) motif enrichment in EglN2‐activated genes, suggesting NRF1 as an EglN2 binding partner. Mechanistically, by forming an activator complex with PGC1α and NRF1 on chromatin, EglN2 promotes the transcription of ferridoxin reductase (FDXR) and maintains mitochondrial function. In addition, FDXR, as one of effectors for EglN2, contributes to breast tumorigenesis in vitro and in vivo. Our findings suggest that EglN2 regulates mitochondrial function in ERα‐positive breast cancer

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner

B55α is a regulatory subunit of the PP2A phosphatase. We have recently found that B55α-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2 triggers degradation of B55α by hydroxylating it at proline 319. In the context of glucose starvation, PHD2 reduces B55α protein levels, which correlates with MDA-MB231 and MCF7 breast cancer cell death. Under these conditions, PHD2 silencing rescues B55α degradation, overcoming apoptosis, whereas in SKBR3 breast cancer cells showing resistance to glucose starvation, B55α knockdown restores cell death and prevents neoplastic growth in vitro. Treatment of MDA-MB231-derived xenografts with the glucose competitor 2-deoxy-glucose leads to tumor regression in the presence of PHD2. Knockdown of PHD2 induces B55α accumulation and treatment resistance by preventing cell apoptosis. Overall, our data unravel B55α as a PHD2 substrate and highlight a role for PHD2-B55α in the response to nutrient deprivation

Rejection of Synchronous Vibrations of AMB System Using Nonlinear Adaptive Control Algorithm with a Novel Frequency Estimator

This paper focuses on the synchronous vibration suppression of an active magnetic bearing (AMB) system without a rotating speed sensor. One of the most intractable problems with AMB systems is the synchronous vibration caused by the mass imbalance of the rotor. Moreover, practically all existing unbalance control algorithms require the rotating speed sensor to determine rotation speed. However, in some unique applications, it is impossible to install and use the rotating speed sensor as intended. This study provided a nonlinear adaptive control (NAC) algorithm and a modified frequency estimator to address the above issues. The proposed approach can suppress current and displacement vibrations by regulating the control structure. The frequency estimator calculates the rotating speed based on the position of the rotor at different moments, which has a quick response time, high precision, and effective tracking. The NAC algorithm can achieve unbalanced control based on the period iteration strategy. Additionally, the Lyapunov method is used to demonstrate the stability of the NAC algorithm. Finally, the experimental and simulation results also confirm the effectiveness and reliability of the overall control scheme. The results from simulations and experiments indicate that the novel frequency estimator can track the speed accurately and that its error can be regulated to within ±0.05 Hz. The overall control schema can reduce the displacement vibration’s amplitude by 72.2% and the current vibration’s amplitude by 65.6%

Rejection of Synchronous Vibrations of AMB System Using Nonlinear Adaptive Control Algorithm with a Novel Frequency Estimator

This paper focuses on the synchronous vibration suppression of an active magnetic bearing (AMB) system without a rotating speed sensor. One of the most intractable problems with AMB systems is the synchronous vibration caused by the mass imbalance of the rotor. Moreover, practically all existing unbalance control algorithms require the rotating speed sensor to determine rotation speed. However, in some unique applications, it is impossible to install and use the rotating speed sensor as intended. This study provided a nonlinear adaptive control (NAC) algorithm and a modified frequency estimator to address the above issues. The proposed approach can suppress current and displacement vibrations by regulating the control structure. The frequency estimator calculates the rotating speed based on the position of the rotor at different moments, which has a quick response time, high precision, and effective tracking. The NAC algorithm can achieve unbalanced control based on the period iteration strategy. Additionally, the Lyapunov method is used to demonstrate the stability of the NAC algorithm. Finally, the experimental and simulation results also confirm the effectiveness and reliability of the overall control scheme. The results from simulations and experiments indicate that the novel frequency estimator can track the speed accurately and that its error can be regulated to within ±0.05 Hz. The overall control schema can reduce the displacement vibration’s amplitude by 72.2% and the current vibration’s amplitude by 65.6%

Bone morphogenetic protein-2 incorporated calcium phosphate graft promotes peri-implant bone defect healing in dogs: A pilot study

Objectives: The evaluation of three different drug delivery modes of bone morphogenetic protein-2 (BMP-2) in healing peri-implant bone defects in beagle dogs. BMP-2 was incorporated in or onto calcium phosphate (CaP) granules in various ways: (i) directly on the outer layer of granules CaP: as an adsorbed depot; (ii) during the entire precipitation process of CaP: an internally incorporated depot; or (iii) during the biomimetic coating precipitation of BMP-2 on the surface of CaP granules: as a coating incorporated depot. Material and Methods: After extraction of the lower molars and wound healing in 6 male beagle dogs, 36 implants were placed (n = 6 animal per group). Peri-implant bone defects were induced. The following treatment groups were evaluated: no treatment; air abrasive surface cleaning (SC) using hydroxyapatite; SC and the subsequent filling of the defect with CaP without BMP-2; SC plus the subsequent filling of the defect with CaP adsorbed BMP-2; SC plus the subsequent filling of the defect with CaP internally incorporated BMP-2; SC plus the subsequent filling of the defect with CaP coating incorporated BMP-2. Histological and histomorphometric analyses were carried out to quantify and compare the changes in bone tissue surrounding the treated implants. Results: In Group 1 with no treatment, four implants were lost. Group 5 with the SC and the subsequent filling of the defect with internally incorporated BMP-2 biomimetically prepared CaP (BioCaP), whereby the BMP-2 is incorporated in the entire volume of all BioCaP particles, showed overall the best results to regenerate bone around the implants. Conclusion: This study concluded that the group treated with SC plus the subsequent filling of the defect with CaP BMP-2 internally incorporated BMP-2, whereby BMP-2 has been incorporated in the entire volume of all CaP particles, showed overall the best results when aiming to regenerate bone around the implants