scholarly journals Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Xuehui Hong ◽  
He Huang ◽  
Xingfeng Qiu ◽  
Zhijie Ding ◽  
Xing Feng ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Inverse Correlation ◽  
Cancer Development ◽  
Posttranslational Regulation ◽  
Mice Model ◽  
Human Colorectal Cancer ◽  
Protein Levels ◽  
Lysine Specific Demethylase ◽  
Tumor Growth And Metastasis ◽  
Cancer Tissues

RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development.

scholarly journals Targeting posttranslational modifications of RioK1 inhibits the progression of colorectal and gastric cancers

2017 ◽  
Author(s):  
Xuehui Hong ◽  
He Huang ◽  
Zhijie Ding ◽  
Xing Feng ◽  
Yuekun Zhu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Posttranslational Modifications ◽  
Half Life ◽  
Inverse Correlation ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Posttranslational Regulation ◽  
Protein Levels ◽  
Lysine Specific Demethylase ◽  
Tumor Growth And Metastasis

AbstractRioK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RioK1 is methylated at K411 by SETD7 methyltransferase, and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RioK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RioK1. FBXO6 specifically interacts with K411-methylated RioK1 through its FBA domain to induce RioK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RioK1 at T410, which stabilizes RioK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RioK1. Functional experiments demonstrate the RioK1 methylation reduces the tumor growth and metastasis in CRC and GC. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human CRC tissues. Therefore, this study highlights the importance of a RioK1 methylation-phosphorylation switch in determining CRC and GC development.

scholarly journals NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Tsuyoshi Waku ◽  
Nanami Nakamura ◽  
Misaki Koji ◽  
Hidenori Watanabe ◽  
Hiroki Katoh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Rectal Adenocarcinoma ◽  
26S Proteasome ◽  
Cancer Development ◽  
20S Proteasome ◽  
Cancer Cell Growth ◽  
Protein Levels ◽  
Cancer Tissues

ABSTRACT Proteasomes are essential protease complexes that maintain cellular homeostasis, and aberrant proteasomal activity supports cancer development. The regulatory mechanisms and biological function of the ubiquitin-26S proteasome have been studied extensively, while those of the ubiquitin-independent 20S proteasome system remain obscure. Here, we show that the cap ’n’ collar (CNC) family transcription factor NRF3 specifically enhances 20S proteasome assembly in cancer cells and that 20S proteasomes contribute to colorectal cancer development through ubiquitin-independent proteolysis of the tumor suppressor p53 and retinoblastoma (Rb) proteins. The NRF3 gene is highly expressed in many cancer tissues and cell lines and is important for cancer cell growth. In cancer cells, NRF3 upregulates the assembly of the 20S proteasome by directly inducing the gene expression of the 20S proteasome maturation protein POMP. Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increases p53 activities for tumor suppression, including cell cycle arrest and induction of apoptosis. Furthermore, protein stability and cell viability assays using two distinct proteasome inhibitor anticancer drugs, the 20S proteasome inhibitor bortezomib and the ubiquitin-activating enzyme E1 inhibitor TAK-243, show that the upregulation of the NRF3-POMP axis leads to ubiquitin-independent proteolysis of p53 and Rb and to impaired sensitivity to bortezomib but not TAK-243. More importantly, the NRF3-POMP axis supports tumorigenesis and metastasis, with higher NRF3/POMP expression levels correlating with poor prognoses in patients with colorectal or rectal adenocarcinoma. These results suggest that the NRF3-POMP-20S proteasome assembly axis is significant for cancer development via ubiquitin-independent proteolysis of tumor suppressor proteins.

scholarly journals Increased Expression of eEF1A2 and PI3K-Akt Signaling Pathway Genes Promotes The Progression of Cervical Cancer

2021 ◽  
Author(s):  
Huizhen Xin ◽  
Huan Pan ◽  
Xiangyi Zhe ◽  
Chunhe Zhang ◽  
Hongtao Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Protein Expression ◽  
Akt Signaling ◽  
Cancer Development ◽  
Akt Signaling Pathway ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Cervical Cancer Development ◽  
Cancer Tissues ◽  
Chronic Cervicitis

Abstract Objective: This study sought to explore the mRNA and protein expression levels of eukaryotic translation elongation factor 1 alpha 2 (eEF1A2) and members of the PI3K-Akt signaling pathway in the context of cervical cancer. We sought to clarify the expression of eEF1A2, PI3K, Akt during cervical cancer tumorigenesis and development.Methods: Samples from 72 cases of cervical cancer were collected, as well as 46 cases of cervical intraepithelial neoplasia (CIN), which reflects the continuous process of cervical cancer development, divided into CIN I, CIN II, CIN III, and 40 cases of chronic cervicitis. qRT-PCR was to detect the mRNA levels of eEF1A2, PI3K, and Akt, with β-actin used as an internal control. eEF1A2, PI3K, p-Akt protein levels in cervical cancer, CIN, and chronic cervicitis tissues were detected by immunohistochemical. eEF1A2, PI3K and p-Akt protein expression levels in HeLa, SiHa, and human umbilical vein endothelial cells were detected by western blot.Results: qRT-PCR results showed that the level of mRNA expression of eEF1A2, PI3K, and Akt was higher in cervical cancer tissues than that in normal cervical tissues. Immunohistochemistry results showed that the eEF1A2, PI3K, and p-Akt protein levels were higher in cervical cancer tissues than in cervical chronic cervicitis tissues. The differences were statistically significant (P < 0.05). The expression of eEF1A2, PI3K, and p-Akt protein was higher in HeLa and SiHa cervical cell lines than that in normal epithelial cells.Conclusion: Together, these results suggest that the aberrant expression of eEF1A2, PI3K, and Akt may play a role in cervical cancer development and tumorigenesis.

Plexin domain containing protein 2 is more expressed within the invasive area of human colorectal cancer tissues

Human Cell ◽  
2021 ◽  
Author(s):  
Yasuhiko Hamada ◽  
Akiko Eguchi ◽  
Kyosuke Tanaka ◽  
Masaki Katsurahara ◽  
Noriyuki Horiki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Human Colorectal Cancer ◽  
Cancer Tissues

Su2024 Association of Microbial Imbalance and Colorectal Cancer Development Using Min Mice Model

2015 ◽  
Vol 148 (4) ◽  
pp. S-577
Author(s):  
Johan Gagnière ◽  
Jennifer Raisch ◽  
nicolas parisot ◽  
Bruno Pereira ◽  
Virginie Bonnin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Development ◽  
Mice Model

scholarly journals Fine-tuning autophagy: from transcriptional to posttranslational regulation

2016 ◽  
Vol 311 (3) ◽  
pp. C351-C362 ◽  
Author(s):  
Joëlle Botti-Millet ◽  
Anna Chiara Nascimbeni ◽  
Nicolas Dupont ◽  
Etienne Morel ◽  
Patrice Codogno
Keyword(s):  
Posttranslational Modifications ◽  
Inflammatory Responses ◽  
Chronic Inflammatory Disease ◽  
Autophagic Vacuole ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Eukaryotic Cells ◽  
Posttranslational Regulation ◽  
Atg Proteins ◽  
Diabetes And Obesity

Macroautophagy (hereafter called autophagy) is a vacuolar lysosomal pathway for degradation of intracellular material in eukaryotic cells. Autophagy plays crucial roles in tissue homeostasis, in adaptation to stress situations, and in immune and inflammatory responses. Alteration of autophagy is associated with cancer, diabetes and obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. Autophagy is controlled by autophagy-related (ATG) proteins that act in a coordinated manner to build up the initial autophagic vacuole named the autophagosome. It is now known that the activities of ATG proteins are modulated by posttranslational modifications such as phosphorylation, ubiquitination, and acetylation. Moreover, transcriptional and epigenetic controls are involved in the regulation of autophagy in stress situations. Here we summarize and discuss how posttranslational modifications and transcriptional and epigenetic controls regulate the involvement of autophagy in the proteostasis network.

scholarly journals MicroRNA-154 Inhibits the Growth and Invasion of Gastric Cancer Cells by Targeting DIXDC1/WNT Signaling

2018 ◽  
Vol 26 (6) ◽  
pp. 847-856 ◽  
Author(s):  
Jifu Song ◽  
Zhibin Guan ◽  
Maojiang Li ◽  
Sha Sha ◽  
Chao Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Inverse Correlation ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Gastric Cancer Cells ◽  
Cancer Cell Growth ◽  
Cancer Tissues

MicroRNAs (miRNAs) have emerged as pivotal regulators of the development and progression of gastric cancer. Studies have shown that miR-154 is a novel cancer-associated miRNA involved in various cancers. However, the role of miR-154 in gastric cancer remains unknown. Here we aimed to investigate the biological function and the potential molecular mechanism of miR-154 in gastric cancer. We found that miR-154 was significantly downregulated in gastric cancer tissues and cell lines. The overexpression of miR-154 significantly repressed the growth and invasion of gastric cancer cells. Bioinformatics analysis and Dual-Luciferase Reporter Assay data showed that miR-154 directly targeted the 3′-untranslated region of Dishevelled‐Axin domain containing 1 (DIXDC1). Real-time quantitative polymerase chain reaction and Western blot analyses showed that miR-154 overexpression inhibited DIXDC1 expression. An inverse correlation of miR-154 and DIXDC1 was also demonstrated in gastric cancer specimens. Overexpression of miR-154 also significantly suppressed the activation of WNT signaling. Moreover, restoration of DIXDC1 expression significantly reversed the inhibitory effect of miR-154 overexpression on the cell proliferation, invasion, and WNT signaling in gastric cancer cells. Overall, these results suggest that miR-154 inhibits gastric cancer cell growth and invasion by targeting DIXDC1 and could serve as a potential therapeutic target for the treatment of gastric cancer.

scholarly journals FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Mei Ji ◽  
Zhao Zhao ◽  
Yue Li ◽  
Penglin Xu ◽  
Jia Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Inverse Correlation ◽  
Degradation Pathway ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Poor Overall Survival ◽  
Protein Levels ◽  
Ubiquitin E3 Ligase ◽  
Ovarian Tumorigenesis ◽  
F Box Protein

AbstractRNASET2 (Ribonuclease T2) functions as a tumor suppressor in preventing ovarian tumorigenesis. However, the mechanisms underlying the regulation of RNASET2 protein are completely unknown. Here we identified the F-box protein FBXO6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin E3 ligase for RNASET2. We found that the interaction between FBXO6 and RNASET2 induced RNASET2 instability through the ubiquitin-mediated proteasome degradation pathway. FBXO6 promoted K48-dependent ubiquitination of RNASET2 via its FBA domain. Through analysis of the TCGA dataset, we found that FBXO6 was significantly increased in ovarian cancer tissues and the high expression of FBXO6 was related to the poor overall survival (OS) of ovarian cancer patients at advanced stages. An inverse correlation between the protein levels of FBXO6 and RNASET2 was observed in clinic ovarian cancer samples. Depletion of FBXO6 promoted ovarian cancer cells proliferation, migration, and invasion, which could be partially reversed by RNASET2 silencing. Thus, our data revealed a novel FBXO6-RNASET2 axis, which might contribute to the development of ovarian cancer. We propose that inhibition of FBXO6 might represent an effective therapeutic strategy for ovarian cancer treatment.

Dysregulation of ECRG4 is associated with malignant properties and of prognostic importance in human gastric cancer

2021 ◽  
pp. 1-12
Author(s):  
Yanjie You ◽  
Shengjuan Hu
Keyword(s):  
Gastric Cancer ◽  
Prognostic Significance ◽  
Statistical Analyses ◽  
Human Gastric Cancer ◽  
Advanced Tumor Stage ◽  
Protein Levels ◽  
Cancer Pathogenesis ◽  
Advanced Tumor ◽  
Cancer Tissues ◽  
The Impact

BACKGROUND: We have previously characterized esophageal carcinoma-related gene 4 (ECRG4) as a novel tumor suppressor gene, which is frequently inactivated in nasopharyngeal carcinoma and breast cancer. Nevertheless, the expression status and prognostic significance of ECRG4 maintain elusive in human gastric cancer. Herein, we examined ECRG4 expression profile in gastric cancer and assessed its association with clinicopathological characteristics and patient survival. METHODS: Online data mining, real-time RT-PCR and immunohistochemistry were employed to determined ECRG4 expression at transcriptional and protein levels in tumors vs. noncancerous tissues. Statistical analyses including the Kaplan-Meier survival analysis and the Cox hazard model were utilized to detect the impact on clinical outcome. Moreover, ECRG4 expression was silenced in gastric cancer SGC7901 cells, and cell proliferation, colony formation and invasion assays were carried out. RESULTS: ECRG4 mRNA and protein levels were obviously downregulated in cancer tissues than noncancerous tissues. Statistical analyses demonstrated that low ECRG4 expression was found in 34.5% (58/168) of primary gastric cancer tissues, which was associated with higher histological grade (P= 0.018), lymph node metastasis (P= 0.011), invasive depth (P= 0.020), advanced tumor stage (P= 0.002) and poor overall survival (P< 0.001). Multivariate analysis showed ECRG4 expression is an independent prognostic predictor (P< 0.001). Silencing ECRG4 expression promoted gastric cancer cell growth and invasion. Western blot analysis revealed the anti-metastatic functions of ECRG4 by downregulating of E-cadherin and α-Catenin, as well as upregulating N-cadherin and Vimentin. CONCLUSIONS: Our observations reveal that ECRG4 expression is involved in gastric cancer pathogenesis and progression, and may serve as a candidate prognostic biomarker for this disease.

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