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SMYD5 regulates mRNA translation to promote gastric adenocarcinoma (GAC)

ABSTRACT: SMYD5 regulates mRNA translation to promote gastric adenocarcinoma (GAC)

PROVIDER: PRJNA998464 | ENA |

REPOSITORIES: ENA

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SMYD5 regulates mRNA translation to promote gastric adenocarcinoma (GAC)

Project description:Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 at lysine 22 (rpL40K22me3) by the lysine methyltransferase (KMT) SMYD5 regulates mRNA translation output to promote gastric adenocarcinoma (GAC) malignant progression with lethal peritoneal ascites. A biochemical-proteomic strategy identifies the mono-ubiquitin fusion protein partner rpL40 as the principal physiologic substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprograms protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in GAC patient samples and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease including peritoneal carcinomatosis (PC). Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to PI3K/mTOR inhibitors. Finally, combining SMYD5 depletion with PI3K/mTOR inhibition and CAR-T administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived PC. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates evolution of malignant GAC and nominates SMYD5 targeting as part of a potential cornerstone combination therapy to treat a deadly cancer.

2024-03-01 | GSE238257 | GEO

LC-MS targeting the rpL40-Lys22 spanning peptide in rpL40-immunoprecipitated representative protein lysates from tissue biopsies of normal stomach and gastric adenocarcinoma (GAC) from KPPC GAC model mice

Project description:We identified SMYD5 (SET and MYND Domain-Containing Protein 5) physiologically methylates core ribosomal protein L40 at lysine 22 (rpL40K22me3).In mouse GAC model, we observed rpL40K22me3 stoichiometry is saturating in both normal and GAC tissue.

2024-06-04 | PXD052359 | Pride

Integrated proteome and phosphoproteome analysis of gastric adenocarcinoma reveals molecular signatures capable of stratifying patient outcome

Project description:Lymph node metastasis is one of the main causes for the low survival rate of gastric cancer patients. Exploring key proteins players in the progression of gastric adenocarcinoma (GAC) may provide new prognostic parkers and therapeutic strategies. we applied proteomic analysis to compare tumor tissues from GAC patients with or without lymph node metastasis, and captured unique molecular features of GAC patients with LNM. Analysis of the phosphoproteome provided a snapshot of abnormal phosphorylation signaling pathways and abnormal kinases activities. Furthermore, we found that TNXB and SPON1, two ECM proteins are associated with LNM status in GAC patients. Thus, our study suggests a number of proteins and kinases that has the potential to serve as prognosis markers to predict patient outcome.

2023-01-05 | PXD033622 | Pride

Data-Independent Acquisition Mass Spectrometry Identification of Serum-derived Extracellular Vesicle Proteomics for Gastric Adenocarcinoma

Project description:Timely diagnosis of gastric adenocarcinoma (GAC) can effectively prevent the deterioration of the disease and significantly improve the survival rate of patients. Currently, tumor markers used in clinical practice cannot meet the needs of patients, and it is urgent to develop biomarkers with high sensitivity and specificity to guide clinical diagnosis. In this study, serum samples from 33 patients with GAC and 19 healthy persons were collected. EVs were extracted by ultracentrifugation and EV protein expression profiles were obtained by DIA quantitative mass spectrometry. Multi-group differential protein expression analysis showed that 23 intersecting proteins had the same expression trend, among which 15 EV proteins were chosen as candidate biomarkers for GAC diagnosis. Afterward, a subset of 2 to 6 proteins was randomly selected as features for logistic regression modeling. To verify the diagnostic performance of these models, serums from a new cohort of 12 patients with gastric cancer and 18 healthy controls were collected, and the EV protein were quantified using the same method. We finally found a panel consisting of six proteins that performed the best as classifier. We also tried to discover biomarkers for diagnosis of advanced stage in GAC, and the results showed a three-protein panel had the best classification performance. In conclusion, we identified new protein biomarker panels from serum EVs for early diagnosis of gastric cancer that worth further validation.

2023-03-11 | PXD027535 | Pride

Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression

Project description:Understanding how the tumor microenvironment (TME) is orchestrated along the continuum of gastric adenocarcinoma (GAC) may uncover novel therapeutic strategies. Here, we performed comprehensive single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and phenotypes during tumorigenesis and progression. IgA+ plasma cells appear to be the most active regulators in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominated the late-stage GACs. We discover six TME ecotypes, four of which are unique to the premalignant/progression in the continuum, with two ecotypes, identified in primary GACs, showing strong associations with histopathologic, genomic characteristics and prognosis. Extensive stromal remodeling is evident with GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) correlates with aggressive phenotypes and poor survival and SDC2 overexpression in CAFs contributes to tumor growth. This study illustrates a roadmap of the GAC TME and highlights potential targets for further investigation.

2023-06-10 | GSE234129 | GEO

LC-MS targeting the rpL40-Lys22 spanning peptide in rpL40-immunoprecipitated KKLS human gastric cancer cell extracts

Project description:We identified SMYD5 (SET and MYND Domain-Containing Protein 5) physiologically methylates core ribosomal protein L40 at lysine 22 (rpL40K22me3). rpL40K22me3 depletion upon SMYD5 knockdown in GAC KKLS cells was observed by targeted-mass spectrometry of immunoprecipitated rpL40.

2024-06-04 | PXD052358 | Pride

Chronic inflammation is a risk factor for gastric carcinogenesis after Helicobacter pylori eradication [miRNA]

Project description:Even after endoscopic treatment of early gastric adenocarcinoma (GAC) and eradication of Helicobacter pylori (H. pylori), some patients develop a metachronous recurrence (MR), the mechanism of which is still unknown. To elucidate the mechanism and risk factors for MR, we analyzed gene expression at multiple locations of the gastric mucosa, considering the heterogeneity of gastric mucosal damage caused by H. pylori infection and investigated the mechanism and risk factors for MR.

2022-12-31 | GSE190455 | GEO

Chronic inflammation is a risk factor for gastric carcinogenesis after Helicobacter pylori eradication [RNA-seq]

2022-12-31 | GSE190449 | GEO

MicroRNA expression of primary gastric adenocarcinoma compared to non-cancer gastric tissue

Project description:Identification of the microRNA signature associated with human gastric adenocarcinoma.

2013-09-01 | GSE26595 | GEO

MicroRNA expression of primary gastric adenocarcinoma compared to non-cancer gastric tissue

Project description:Identification of the microRNA signature associated with human gastric adenocarcinoma. Total RNA obtained from 60 primary gastric cancer tissues and 8 surrounding non-cancer tissues was used for microarray analysis. For validation, real-time RT-PCR was performed.

2013-09-01 | E-GEOD-26595 | biostudies-arrayexpress

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