Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells

Thangjam, Gagan; Birmpas, Charalampos; Barabutis, Nektarios; Gregory, Betsy; Clemens, Mary Ann; Newton, Joseph; Fulton, David; Catravas, John D.

doi:10.1152/ajplung.00054.2016

Cited by 38 publications

(32 citation statements)

References 36 publications

(50 reference statements)

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“…For example, Lysine acetylation on histones could change local chromatin structure for transcription factors to bind and initiate gene transcription ( Jin et al, 2011 ). Lysine acetylation on non-histone proteins including enzymes and transcription factors induced metabolic rewiring and gene transcription, and affected cell proliferation, apoptosis, and metastasis ( Leo et al, 2019 ; Thangjam et al, 2016 ; Wang B. et al, 2020 ; He et al, 2019 ). These findings indicated that lysine acetylation was an important factor in cancer development.…”

Section: Introductionmentioning

confidence: 99%

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Zhao

Zhang

et al. 2020

Front. Genet.

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Lysine acetylation is a vital post-translational modification (PTM) of proteins, which plays an important role in cancer development. In healthy human liver tissues, multiple non-histone proteins were identified with acetylation modification, however, the role of acetylated proteins in hepatocellular carcinoma (HCC) development remains largely unknown. Here we performed a quantitative acetylome study of tumor and normal liver tissues from HCC patients. Overall, 598 lysine acetylation sites in 325 proteins were quantified, and almost 59% of their acetylation levels were significantly changed. The differentially acetylated proteins mainly consisted of non-histone proteins located in mitochondria and cytoplasm, which accounted for 42% and 24%, respectively. Bioinformatics analysis showed that differentially acetylated proteins were enriched in metabolism, oxidative stress, and signal transduction processes. In tumor tissues, 278 lysine sites in 189 proteins showed decreased acetylation levels, which occupied 98% of differentially acetylated proteins. Moreover, we collected twenty pairs of tumor and normal liver tissues from HCC male patients, and found that expression levels of SIRT1 (p = 0.002), SIRT2 (p = 0.01), and SIRT4 (p = 0.045) were significantly up-regulated in tumor tissues. Over-expression of possibly accounted for the widespread deacetylation of non-histone proteins identified in HCC tumor tissues, which could serve as promising predictors of HCC. Taken together, our work illustrates abundant differentially acetylated proteins in HCC tumor tissues, and offered insights into the role of lysine acetylation in HCC development. It provided potential biomarker and drug target candidates for clinical HCC diagnosis and treatment.

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Section: Introductionmentioning

confidence: 99%

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Zhao

Zhang

et al. 2020

Front. Genet.

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“…Because, NKILA transcript normally suppress the activity of NF-κB as mentioned above. HSP90 is responsible for the drug resistance, is also in ammatory response in cancer mainly and these kind of conditions are closely related with the NF-κB protein levels which known as poor prognosis marker in the cancer patients (5). Under these circumstances our ndings suggest that HSP90 levels might increase as response to NKILA inhibition because of close relation with the NF-κB subunits.…”

Section: Discussionmentioning

confidence: 60%

“…In breast cancer patients NF-κB was found to be signi cantly activated and associated with oncogenesis (3). NF-κB is directly associated with HSP90 (heat shock protein 90) (5), which is another important antiapoptotic molecule (6). NF-κB can bind to HSP90 promoter in cancer cells (7), or HSP90 may involve the IKK (IκB kinase) activation (8) thus HSP90 and NF-κB molecules are expected to be correlated and provide cancer cell survival.…”

Section: Introductionmentioning

confidence: 99%

NKILA Regulates HSP90α, NF-κB subunits and β-Catenin Expressions in the MCF-7 Cells

Tibatan

Eö

2021

Preprint

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Background: Non-coding RNAs are increasingly investigated and have great potential for diagnose, prognosis and treatment of cancer. Thus, we investigated the possible relation between NF-κB suppressor-NKILA and HSP90, NF-κB and β-catenin molecules in the MCF-7. HSP90 is a compelling stress protein and together with β-catenin and NF-κB molecules it can be responsible for the cancer cell development. However, NKILA is a novel molecule and there is not comprehensive data about it unlike HSP90, β-catenin and NF-κB alone. Therefore, we suggest that there might be a correlation between NKILA and these proteins. Methods and Results: To investigate the NKILA role on these proteins we inhibited the NKILA by using transfection. MCF-7 cells transfected with NKILA-siRNA and incubated for 5 hours. Then, cells were collected and proteins were extracted to be separated in SDS-PAGE. Aforementioned proteins of siRNA transfected group were evaluated by comparing their band intensities with the control group protein bands by immunoblotting. According to this, HSP90 and NF-κB/p105, NF-κB/p65 and NF-κB/p50 subunits significantly increased while β-catenin significantly decreased after NKILA inhibition.Conclusion:, For the first time we demonstrate that HSP90 and beta-catenin is associated with NKILA levels and this may highly related with canonical NF-κB pathway in MCF-7 cells. These novel findings may have important implications in cancer cells development and might present important hints for the future studies about the cancer cell targeted therapy.

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“…Having identified putative KIRA6 off-targets, we then wished to explore their possible relevance in the pro-inflammatory pathway targeted by KIRA6. We then focused our attention on the molecular chaperones HSP60 and HSP90 for different reasons; i) with the exception of actin, both molecular chaperones were the top-listed ATP-binding proteins identified by LC-MS/MS (Table 1), ii) HSP90 is a known regulator of NF-B-driven inflammatory signaling (Thangjam et al 2016;Qing et al 2007;Gopalakrishnan, Matta, and Chaudhary 2013); and iii) the cytosolic fraction of HSP60 has been recently shown to promote CXCL8 production by cancer cells by positively regulating NF-B (Chun et al 2010).…”

Section: Hsp60 Contributes To the Activation Of Nf-b Signaling And Cmentioning

confidence: 99%

The IRE1 Inhibitor Kira6 Curtails The Inflammatory Trait Of Immunogenic Anticancer Treatments By Targeting Hsp60 Independent Of IRE1

Rufo

Korovesis

Eygen

et al. 2020

Preprint

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Cellular stress evoked by immunogenic anticancer treatments engaging the unfolded protein response (UPR) can elicit inflammation with conflicting therapeutic outcomes. To define cell-autonomous mechanisms coupling the UPR to molecular mediators of inflammation, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic-treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated NF-κB/AP-1-inflammatory pathways, which were abolished by the IRE1α-kinase inhibitor KIRA6. Cell-free fractions of chemotherapy and KIRA6 co-treated cancer cells were deprived of pro-inflammatory/chemoattractant factors and failed to mobilize innate immune cells. Strikingly, these potent KIRA6 anti-inflammatory effects were found to be independent of IRE1α. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the NF-κB pathway. In sum, our study unravels that inflammation evoked by immunogenic treatments is curtailed by KIRA6 independently of IRE1α and further suggests great caution in interpreting the anti-inflammatory action of IRE1α chemical inhibitors.

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Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells

Abstract: Hsp90 inhibition suppresses NF-B transcriptional activation via Sirt-2 in human lung microvascular endothelial cells.

Cited by 38 publications

References 36 publications

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

NKILA Regulates HSP90α, NF-κB subunits and β-Catenin Expressions in the MCF-7 Cells

The IRE1 Inhibitor Kira6 Curtails The Inflammatory Trait Of Immunogenic Anticancer Treatments By Targeting Hsp60 Independent Of IRE1

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