Transmembrane Protein 100 Inhibits the Progression of Colorectal Cancer by Promoting the Ubiquitin/Proteasome Degradation of HIF-1α

Ying, Zheng; Zhao, Yitong; Jiang, Jiong; Zou, Baicang; Dong, Lei

doi:10.3389/fonc.2022.899385

Cited by 8 publications

(2 citation statements)

References 37 publications

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“…The prognosis for ESCC remains challenging, partially due to the absence of prognostic biomarkers capable of identifying high-risk patients and facilitating the assignment of risk-appropriate monitoring and treatment regimens. TMEM100 is well established as an oncogene, as demonstrated by its inhibitory role in colorectal cancer progression through the promotion of ubiquitin/proteasome degradation of hypoxia-inducible factor-1 alpha[ 22 ]. The downregulation of TMEM100, mediated by histone deacetylase 6, expedites the development and progression of non-small cell lung cancer[ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma

Xu,

Dang,

Kong

et al. 2024

World J Clin Oncol

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BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). AIM To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. METHODS Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. RESULTS In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. CONCLUSION TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.

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Section: Discussionmentioning

confidence: 99%

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma

Xu,

Dang,

Kong

et al. 2024

World J Clin Oncol

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“…UPS dysregulation due to E3-related genes (E3RGs) mutations is strongly associated with poor cancer survival (Seeler and Dejean, 2017). In Colon Cancer pathogenesis, emerging studies have found the critical role of E3-related proteins, such as ZNF280A (Tian et al, 2022, 14), TMEM100 (Zheng et al, 2022), RNF43 (Schatoff et al, 2017;Siraj et al, 2022), and TRIM52 (Guo et al, 2022). Additionally the E3 ligases, RNF128 (Zhuang et al, 2022, 128) and TRIM29 (Jiang et al, 2021) have been reported in the regulation of PI3K/Akt pathway in colorectal cancer.…”

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confidence: 99%

A new prognostic signature of 11 E3-related genes for colon cancer related to the immune microenvironment and somatic mutation

Jiang,

Dong,

et al. 2023

Preprint

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Background Colon Cancer (COAD) is a common tumor in the gastrointestinal tract with a poor prognosis. It has been reported that ubiquitin-dependent modification systems influence tumor genesis and progression in various malignancies. Methods We collected the RNA expression data of the E3RGs from the TCGA-COAD program, used the “limma” R package to get differentially expressed E3RGs between COAD and healthy patients. Then we constructed the prognostic signature and calculated the risk score with univariate COX regression analysis and the LASSO analysis. We used a nomogram model to examine the predictive ability of the predictive model to predict OS rates at 1, 3, and 5 years. Next, we explored the significance of the predictive model under the stratified analysis. At last, we used bioinformatics and statistical methods to find some potential mechanisms in COAD cancer. Results We screened 137 E3-related genes (E3RGs), including 89 upregulated and 48 down-regulated E3RGs. Eleven genes (CORO2B, KCTD9, RNF32, BACH2, RBCK1, DPH7, WDR78, UCHL1, TRIM58, WDR72, and ZBTB18) were identified for the construction of prognostic signatures using univariate and multivariate Cox regression analysis, and lasso regression analysis. Kaplan-Meier curve analysis with log-rank testing showed a worse prognosis for patients with high risk based on the constructed E3RGs-based classifiers both in the train and test sets (P = 1.037e-05, P = 5.704e-03), and the proportion under ROC curves (AUC) was significant both in training and test groups (5-year AUC, 0.728 versus 0.892). Based on a stratified analysis, this 11-ERGs signature was a novel and attractive prognostic model independent of several clinicopathological parameters (age, sex, stage, TNM) in COAD. The enrichment and TME analysis of the signature confirmed that this signature might provide insight into the molecular mechanisms in COAD cancer. Conclusions We developed a novel independent risk model consisting of 11 ERGs and verified the effectiveness of this model in predicting the prognosis of COAD patients, providing important insights into survival prediction in COAD and several promising targets for COAD therapy.

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Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

Fang

Han

Chen

et al. 2023

Sig Transduct Target Ther

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Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (KrasLSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a “Yin-Yang” counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the “Yin-Yang” homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

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Transmembrane Protein 100 Inhibits the Progression of Colorectal Cancer by Promoting the Ubiquitin/Proteasome Degradation of HIF-1α

Cited by 8 publications

References 37 publications

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma

Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma

A new prognostic signature of 11 E3-related genes for colon cancer related to the immune microenvironment and somatic mutation

Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

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