Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

Li, Zhongrui; Zhang, Lan; Liu, Dongrui; Yang, Zhanghui; Di, Xuan; Zhang, Yi

doi:10.1038/s41420-021-00622-w

Cited by 11 publications

(9 citation statements)

References 33 publications

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“…Among them, CENPA plays a significant role in cancer. For example, the upregulation of the CENPA/Myc/Bcl2 axis significantly enhances the sensitivity of retinoblastoma cells to cisplatin ( 12 ). Furthermore, CENPA may function as a prognostic biomarker in lung adenocarcinoma (LUAD) ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer and Single-Cell Analysis Reveals CENPL as a Cancer Prognosis and Immune Infiltration-Related Biomarker

et al. 2022

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BackgroundCentromere protein L (CENPL) is an important member of the centromere protein (CENP) family. However, the correlation between CENPL expression and cancer development and immune infiltration has rarely been studied. Here, we studied the role of CENPL in pan-cancer and further verified the results in lung adenocarcinoma (LUAD) through in vitro experiments.MethodsThe CENPL expression level was studied with TIMER 2.0 and Oncomine databases. The potential value of CENPL as a diagnostic and prognostic biomarker in pan-cancer was evaluated with the TCGA database and GEPIA. The CENPL mutation character was analyzed using the cBioPortal database. The LinkedOmics and CancerSEA databases were used to carry out the function analysis of CENPL. The role of CENPL in immune infiltration was studied using the TIMER and TISIDB websites. Moreover, the expression of CENPL was detected through RT-qPCR and Western blotting. Immunohistochemistry was used to evaluate the infiltration level of CD8+ T cells. Cell proliferation was detected by EdU and CCK8. A flow cytometer was used to analyze the influence of CENPL in cell cycle and apoptosis.ResultsCENPL was increased in most of the cancers. The upregulation and mutation of CENPL were associated with a poorer prognosis in many cancers. The results showed a significant positive correlation between CENPL and myeloid-derived suppressor cell (MDSC) infiltration and a negative correlation between CENPL and T-cell NK infiltration in most of the cancers. CENPL regulated cell proliferation and cell cycle, and was negatively correlated with the inflammation level of LUAD. The in vitro experiments suggested that CENPL was increased in LUAD tissue and cell lines. There was a negative correlation between CENPL expression and CD8+ T-cell infiltration. The knockdown of CENPL significantly suppressed the expression of CDK2 and CCNE2, and induced G0/G1 arrest and apoptosis of LUAD.ConclusionsCENPL may function as a potential biomarker and oncogene in pan-cancer, especially LUAD. Furthermore, CENPL was associated with immune cell infiltration in pan-cancer, providing a potential immune therapy target for tumor treatment.

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Section: Introductionmentioning

confidence: 99%

Pan-Cancer and Single-Cell Analysis Reveals CENPL as a Cancer Prognosis and Immune Infiltration-Related Biomarker

et al. 2022

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“…Aberrant expression of NRMT (N-terminal regulator of chromatin condensation 1 methyltransferase) has been reported in various cancers [ 52 , 53 ]. NRMT controls the expression of CENPA through a promoter region of CENPA [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…NRMT controls the expression of CENPA through a promoter region of CENPA [ 54 ]. Furthermore, CENPA induces the transcription of Myc and elevates the expression of Bcl2 in retinoblastoma cells [ 53 ]. Importantly, aberrant expression of the NRTM/CENPA/Bcl2 axis developed in cisplatin (CDDP) resistance of retinoblastoma cells [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Super-Enhancer-Based Analysis: Identification of Prognostic Genes in Oral Squamous Cell Carcinoma

Saito

Asai

Tanaka

et al. 2022

IJMS

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Advanced-stage oral squamous cell carcinoma (OSCC) patients are treated with combination therapies, such as surgery, radiation, chemotherapy, and immunotherapy. However, OSCC cells acquire resistance to these treatments, resulting in local recurrence and distant metastasis. The identification of genes involved in drug resistance is essential for improving the treatment of this disease. In this study, we applied chromatin immunoprecipitation sequencing (ChIP-Seq) to profile active enhancers. For that purpose, we used OSCC cell lines that had been exposed to cetuximab for a prolonged period. In total, 64 chromosomal loci were identified as active super-enhancers (SE) according to active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) ChIP-Seq. In addition, a total of 131 genes were located in SE regions, and 34 genes were upregulated in OSCC tissues by TCGA-OSCC analysis. Moreover, high expression of four genes (C9orf89; p = 0.035, CENPA; p = 0.020, PISD; p = 0.0051, and TRAF2; p = 0.0075) closely predicted a poorer prognosis for OSCC patients according to log-rank tests. Increased expression of the four genes (mRNA Z-score ≥ 0) frequently co-occurred in TCGA-OSCC analyses. The high and low expression groups of the four genes showed significant differences in prognosis, suggesting that there are clear differences in the pathways based on the underlying gene expression profiles. These data indicate that potential stratified therapeutic strategies could be used to overcome resistance to drugs (including cetuximab) and further improve responses in drug-sensitive patients.

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“…26, 160.35, 143.33, 109.58, 61.00, 36.90, 28.22, 14.14. (17). t-BuOK (448 mg, 4.0 mmol) was added to a stirred anhydrous DMF solution (15 mL) of 16 (286 mg, 1.0 mmol) in portion.…”

Section: (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)prop...mentioning

confidence: 99%

“…16 In addition, NTMT1 serves as an oncogene for neuroblastoma, as its knockdown suppresses the tumor growth and increases the sensitivity to cisplatin treatment. 17 More recently, NTMT1 has demonstrated an important role in stem cell regulation. Knockout of NTMT1 in mice results in premature aging phenotypes, including neurodegeneration by depleting neuronal stem cell pools.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies of Venglustat on NTMT1 Inhibition

et al. 2023

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The protein N-terminal methyltransferase 1 (NTMT1) is implicated in neurogenesis, retinoblastoma, and cervical cancer. However, its pharmacological potentials have not been elucidated due to the lack of drug-like inhibitors. Here, we report the discovery of the first NTMT1 in vivo chemical probe GD433 by structure-guided optimization of our previously reported lead compound venglustat. GD433 (IC50 = 27 ± 1.1 nM) displays improved potency and selectivity than venglustat across biochemical, biophysical, and cellular assays. GD433 also displays good oral bioavailability and can serve as an in vivo chemical probe to dissect the pharmacological roles of Nα methylation. In addition, we also identified a close analogue (YD2160) that is inactive against NTMT1. The active inhibitor and negative control will serve as valuable tools to examine the physiological and pharmacological functions of NTMT1 catalytic activity.

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Knockdown of NRMT enhances sensitivity of retinoblastoma cells to cisplatin through upregulation of the CENPA/Myc/Bcl2 axis

Cited by 11 publications

References 33 publications

Pan-Cancer and Single-Cell Analysis Reveals CENPL as a Cancer Prognosis and Immune Infiltration-Related Biomarker

Pan-Cancer and Single-Cell Analysis Reveals CENPL as a Cancer Prognosis and Immune Infiltration-Related Biomarker

Genome-Wide Super-Enhancer-Based Analysis: Identification of Prognostic Genes in Oral Squamous Cell Carcinoma

Structure–Activity Relationship Studies of Venglustat on NTMT1 Inhibition

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