Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K/AKT/mTOR pathway

Shan, Jixiu; Wang, Zhen; Mo, Qiuping; Long, Jingpei; Fan, Yangfan; Cheng, Liang; Zhang, Tao; Liu, Xiyong; Wang, Xiaochen

doi:10.1016/j.pan.2022.03.002

Cited by 7 publications

(3 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell cycle analysis of ADA2B KO cells by flow cytometry showed increased accumulation at the G0/G1 stage (Figure 3G), corresponding to the enrichment of G1/S transition related genes among ADA2B core targets. Additionally, many MTORC1 signaling genes directly targeted by ADA2B facilitate cancer growth and progression (Figure 3D) (He et al 2019b; Kiss et al 2020; Mo et al 2020; Zhao et al 2020; Shan et al 2022; Feng et al 2023). Known regulators of MM biology, such as EZH2 , ITGB7 , and SETDB1 , were also among the ADA2B core targets (Neri et al 2011; Alzrigat et al 2018a; Qian et al 2023).…”

Section: Resultsmentioning

confidence: 99%

The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma

Chen,

Bhaskara,

et al. 2024

Preprint

View full text Add to dashboard Cite

Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of datasets in the Cancer Dependency Map Project revealed many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA-seq, ATAC-seq, and CUT&RUN results identified pathways directly regulated by ADA2B include MTORC1 signaling, MYC, E2F, and MM-specific MAF oncogenic programs. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma

Chen,

Bhaskara,

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Similarly, the enrichment analysis of DEGs between the high- and low-risk groups involves tumor-related mechanisms. Studies have demonstrated that PI3K/AKT pathway inactivation in PAAD cells can inhibit mutant p53, thus inducing S-phase arrest and apoptosis of PAAD cells [ 34 ]. In addition, there is a close relationship between extracellular matrix (ECM) accumulation and cancer progression, and pancreatic stellate cells play a role in this process.…”

Section: Discussionmentioning

confidence: 99%

A Novel Cuproptosis‐Associated Gene Signature to Predict Prognosis in Patients with Pancreatic Cancer

Jiang

Hou

et al. 2023

BioMed Research International

View full text Add to dashboard Cite

Background. Pancreatic cancer (PAAD) is a malignant tumor with a poor prognosis and lacks sensitive biomarkers for diagnosis and targeted therapy. Cuproptosis, a recently proposed form of cell death based on cellular copper ion concentration, plays a key role in cancer biology. This study is aimed at constructing a risk model for predicting the prognosis of PAAD patients based on cuproptosis-related genes. Methods. Pancreatic-related data from UCSC-TCGA and UCSC-GTEx databases were extracted for analysis, and TCGA-PAAD samples were randomly divided into the training and validation groups. Pearson correlation analysis was used to obtain cuproptosis-related genes coexpressed with 19 copper death genes. Univariate Cox and Lasso regression analyses were used to obtain cuproptosis-related prognostic genes. Multivariate Cox regression analysis was used to construct the final prognostic risk model. The risk score curve, Kaplan-Meier survival curves, and ROC curve were used to evaluate the predictive ability of the Cox risk model. Finally, the functional annotation of the risk model was obtained through enrichment analysis. Results. The Cox risk model has an eight prognostic cuproptosis-related gene signature. Kaplan-Meier survival curves demonstrated that the high-risk group had a shorter survival time. The ROC curve of the risk score was well created to predict one-, three-, and five-year survival rates, and AUC of the risk score was higher than other clinical characteristics. Cox regression analysis revealed that the risk score has an independent prognostic value for PAAD. GSEA reveals specific tumor pathways associated with the risk model (Myc targets v1, mTORC1 signaling, and E2F targets). Conclusions. We constructed a prognostic model containing eight cuproptosis-related genes (AKR1B10, KLHL29, PROM2, PIP5K1C, KIF18B, AMIGO2, MRPL3, and PI4KB) that can accurately predict the prognosis of PAAD patients. The results will provide new perspectives for individualized outcome prediction and new therapy development for PAAD patients.

show abstract

“…However, in cancer cells, DNA damage repair processes, such as nucleotide excision repair, post-replication repair and homologous recombination repair, may counteract the effects of cisplatin, resulting in cisplatin resistance (28). Recent studies have indicated that RRM2, an oncogene, plays a critical role in the proliferation, migration, invasion, and drug resistance of breast cancer cells, small cell lung cancer cells, renal clear cell carcinoma cells, and pancreatic cancer cells (29)(30)(31)(32). In lung adenocarcinoma, suppression of RRM2 also inhibits the proliferation, migration and invasive ability of lung adenocarcinoma cells (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

RRM2‑mediated Wnt/β‑catenin signaling pathway activation in lung adenocarcinoma: A potential prognostic biomarker

Jiang,

Hu,

Pang

et al. 2023

Oncol Lett

View full text Add to dashboard Cite

The present study aimed to investigate the role and mechanism of action of ribonucleotide reductase M2 (RRM2) in lung adenocarcinoma and its potential as a therapeutic target. Data of patients with lung adenocarcinoma from The Cancer Genome Atlas database were collected and analyzed to evaluate the potential of RRM2 as a biomarker. The expression of RRM2 was evaluated in the A549 cell line and its cisplatin-resistant A549/DDP cell line derivative by western blot and reverse transcription-quantitative PCR. The study also investigated cell proliferation and the mechanism by which RRM2 controls cellular cisplatin resistance using CCK-8 and colony-formation assays. In addition, cell migration was assessed using Transwell assays, and the cell cycle and apoptosis were examined using flow cytometry. RRM2 was highly expressed in lung adenocarcinoma and was associated with the clinical TMN stage. Functional enrichment analysis showed that RRM2 was enriched in the cell cycle. Immune cell infiltration analysis identified 12 types of immune cell that exhibited differences between patients expressing different levels of RRM2. Cellular assays revealed higher levels of RRM2 expression in A549/DDP cells than A549 cells, and its expression was induced by cisplatin. RRM2 knockdown decreased cell proliferation and migration, accelerated apoptosis and caused cell cycle arrest in the S-phase, increasing the sensitivity of A549 and A549/DDP cells to cisplatin through the Wnt/β-catenin signaling pathway. Overexpression of β-catenin reduced the effects of RRM2 knockdown on A549 cells. Lung adenocarcinoma growth may be influenced by RRM2 through the Wnt/β-catenin signaling pathway, suggesting a potential pathway for cancer progression.

show abstract

Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K/AKT/mTOR pathway

Cited by 7 publications

References 48 publications

The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma

The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma

A Novel Cuproptosis‐Associated Gene Signature to Predict Prognosis in Patients with Pancreatic Cancer

RRM2‑mediated Wnt/β‑catenin signaling pathway activation in lung adenocarcinoma: A potential prognostic biomarker

Contact Info

Product

Resources

About