Non-thermal plasma induces AKT degradation through turn-on the MUL1 E3 ligase in head and neck cancer

Kim, Sunyong; Kim, Haeng-Jun; Kang, Sung Un; Kim, Yang Eun; Park, Ju Kyeong; Shin, Yoo Seob; Kim, Yeon Soo; Lee, Keunho; Kim, Chul‐Ho

doi:10.18632/oncotarget.5407

Cited by 57 publications

(96 citation statements)

References 28 publications

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“…To investigate how resolution impacted the correlation between human and mouse signature gene estimates, we also collapsed the high resolution human liver cellular composition estimates for each of the 175 deconvoluted samples by summing the estimates across similar cell types in each of the 7 distinct cell classes (Table S2) Figure S1). We found that hepatocyte estimates from mouse liver were positively and highly correlated with the human high resolution hepatocyte 0 population estimate (r = 0.71, p-value = 5.4x10- 28), but not correlated with any of the other three high resolution hepatocyte populations (1, 3 and 4); and was slightly less correlated with the collapsed hepatocyte population estimate (r=0.64, p-value = 1.015x10-21) ( Figure 2F,G). This indicates that the low resolution mouse hepatocyte population corresponds to one of the four human hepatocyte populations/zones potentially due to tissue sampling.…”

Section: Mouse Liver Signature Genes Can Estimate Cellular Compositiomentioning

confidence: 83%

Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants

Mkr

D’Antonio‐Chronowska²,

D’Antonio³

et al. 2019

Preprint

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The Genotype-Tissue Expression (GTEx) resource has contributed a wealth of novel insights into the regulatory impact of genetic variation on gene expression across human tissues, however thus far has not been utilized to study how variation acts at the resolution of the different cell types composing the tissues. To address this gap, using liver and skin as a proof-of-concept tissues, we show that readily available signature genes based on expression profiles of mouse cell types can be used to deconvolute the cellular composition of human GTEx tissues. We then deconvoluted 6,829 bulk RNA-seq samples corresponding to 28 GTEx tissues and show that we are able to quantify cellular heterogeneity, determining both the different cell types present in each of the tissues and how their proportions vary between samples of the same tissue type. Conducting eQTL analyses for GTEx liver and skin samples using cell type composition estimates as interaction terms, we identified thousands of novel genetic associations that had lower effect sizes and were cell-type-associated. We further show that cell-type-associated eQTLs in skin colocalize with melanoma, malignant neoplasm, and infection signatures, indicating variants that influence gene expression in distinct skin cell types play important roles in skin traits and disease. Overall, our study provides a framework to estimate the relative fractions of different cell types in GTEx tissues using signature genes from mouse cell types and functionally characterize human genetic variation that impacts gene expression in a cell-type-specific manner.

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Section: Mouse Liver Signature Genes Can Estimate Cellular Compositiomentioning

confidence: 83%

Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants

Mkr

D’Antonio‐Chronowska²,

D’Antonio³

et al. 2019

Preprint

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show abstract

“…There are various methods of Akt regulation, and one mechanism is Akt degradation. Kim et al (32) reported that non-thermal plasma induced Akt degradation via the ubiquitin-proteasome system, subsequently leading to head and neck cancer cell death. They also demonstrated that cigarette smoke induced normal human lung fibroblast cell apoptosis by Akt protein degradation via the ubiquitin-proteasome system (13).…”

Section: Discussionmentioning

confidence: 99%

Nicotine induces H9C2 cell apoptosis via Akt protein degradation

Huang

Guo

Zhao

et al. 2017

Molecular Medicine Reports

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Smoking is highly associated with cardiovascular diseases. However, the effect of nicotine, a key ingredient in smoking products, on cardiomyocyte apoptosis remains controversial. The present study aims to clarify the role of nicotine on cardiomyocyte cell apoptosis and to investigate the underlying mechanism. In the present study, H9C2 cells were exposed to nicotine at various concentrations (0, 10 and 100 µM) for 48 h. Cell Counting Kit‑8 and TUNEL assays were performed to assess cell viability and apoptosis, respectively, and reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to investigate the mRNA and protein expression. PYR‑41, a ubiquitin E1 inhibitor, was employed to investigate whether the ubiquitin‑proteasome system was involved in the downregulation of Akt. An Akt1 overexpression plasmid was used to demonstrate the role of Akt in H9C2 cells apoptosis. Tetratricopeptide repeat domain 3 (TTC3) small interfering RNA (siRNA) was used to investigate the effect of TTC3 on Akt protein degradation. The results demonstrated that nicotine induced apoptosis in H9C2 cells compared with control cells (P<0.05). The protein level of Akt was downregulated by nicotine in a concentration‑dependent manner (P<0.05). PYR‑41 treatment restored the protein level of Akt. The cell viability was significantly improved by Akt overexpression when cells were exposed to nicotine at 10 µM, compared with control cells. Nicotine also upregulated the level of TTC3 mRNA (P<0.05) and the protein level of Akt, and cell viability was recovered by TTC3 siRNA. In conclusion, the current study demonstrated that nicotine induced H9C2 cell apoptosis via Akt protein degradation, which may be mediated by TTC3.

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“…Mitophagy and mitochondrial dynamics cause frequent changes in both quantity and morphology of cells and organelles . The imbalance of homeostasis is clearly associated with diseases such as Parkinson's disease, viral infection and carcinomas . It was reported that Mul1 mediates the ubiquitination of Akt and HSPA5 to inhibit the development of head and neck cancer .…”

Section: Introductionmentioning

confidence: 99%

“…28 The imbalance of homeostasis is clearly associated with diseases such as Parkinson's disease, viral infection and carcinomas. [29][30][31][32][33] It was reported that Mul1 mediates the ubiquitination of Akt and HSPA5 to inhibit the development of head and neck cancer. 32,33 Herein, we show that Mul1 promotes autophagy flux and suppresses ccRCC development with cell culture models and its loss of expression in ccRCC tissues from patients may lead to the blockade of autophagy flux, development of ccRCC and impairment of survival.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial E3 ubiquitin ligase 1 promotes autophagy flux to suppress the development of clear cell renal cell carcinomas

Yuan

et al. 2019

Cancer Science

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Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors in the urinary system. Surgical intervention is the preferred treatment for ccRCC, but targeted biological therapy is required for postoperative recurrent or metastatic ccRCC. Autophagy is an intracellular degradation system for misfolded/aggregated proteins and dysfunctional organelles. Defective autophagy is associated with many diseases. Mul1 is a mitochondrion‐associated E3 ubiquitin ligase and involved in the regulation of divergent pathophysiological processes such as mitochondrial dynamics, and thus affects the development of various diseases including cancers. Whether Mul1 regulates ccRCC development and what is the mechanism remain unclear. Histochemical staining and immunoblotting were used to analyze the levels of Mul1 protein in human renal tissues. Statistical analysis of information associated with tissue microarray and The Cancer Genome Atlas (TCGA) database was conducted to show the relationship between Mul1 expression and clinical features and survival of ccRCC patients. Impact of Mul1 on rates of cell growth and migration and autophagy flux were tested in cultured cancer cells. Herein we show that Mul1 promoted autophagy flux to facilitate the degradation of P62‐associated protein aggresomes and adipose differentiation‐related protein (ADFP)‐associated lipid droplets and suppressed the growth and migration of ccRCC cells. Levels of Mul1 protein and mRNA were significantly reduced so that autophagy flux was likely blocked in ccRCC tissues, which is potentially correlated with enhancement of malignancy of ccRCC and impairment of patient survival. Therefore, Mul1 may promote autophagy to suppress the development of ccRCC.

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Non-thermal plasma induces AKT degradation through turn-on the MUL1 E3 ligase in head and neck cancer

Cited by 57 publications

References 28 publications

Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants

Cellular deconvolution of GTEx tissues powers eQTL studies to discover thousands of novel disease and cell-type associated regulatory variants

Nicotine induces H9C2 cell apoptosis via Akt protein degradation

Mitochondrial E3 ubiquitin ligase 1 promotes autophagy flux to suppress the development of clear cell renal cell carcinomas

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