MFAP2, upregulated by m1A methylation, promotes colorectal cancer invasiveness via CLK3

Xue, Min; Mi, Shuyi; Zhang, Zizhen; Wang, Hao; Chen, Wenwen; Wei, Wei; Lou, Guochun

doi:10.1002/cam4.5561

Cited by 16 publications

(6 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) to explore differentially methylated peaks within mRNAs by comparing CRC samples and tumor-adjacent normal tissues, and identi ed differentially expressed mRNAs simultaneously. Micro bril-associated protein 2 (MFAP2), whose mRNA is overexpressed and m1A hypermethylated in CRC, was found to promote CRC invasion in our recent study [13].…”

Section: Introductionmentioning

confidence: 79%

m1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

Mi,

Lou,

Chen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Background In recent years, the emphasis has shifted to understanding the role of N1-methyladenosine (m1A) in tumor progression as little is known about its regulatory effect on mRNA and its role in the metastasis of colorectal cancer (CRC). Methods We performed methylated RNA immunoprecipitation sequencing of tumor tissues and tumor-adjacent normal tissues from three patients with CRC to determine the m1A profile of mRNA in CRC. The expression of diaphanous-related formin 3 (DIAPH3) and its correlation with clinicopathological characteristics of CRC were evaluated using immunohistochemistry and online datasets. The role of DIAPH3 in the migration and invasion of CRC cells was evaluated using wound healing assay, Transwell assay and xenograft metastatic model. The downstream targets of DIAPH3 were screened using mass spectrometry. By co-transfecting DIAPH3 siRNA and a keratin 19 (KRT19) ectopic plasmid into CRC cells, the role of DIAPH3-KRT19 signaling axis was confirmed. Results The mRNA level of DIAHP3 and its m1A modifications increased simultaneously in the CRC tissues. In addition, high DIAPH3 expression in CRC tissues is significantly associated with metastasis and progression to an advanced stage. After the knockdown of DIAPH3, the migration and invasion capabilities of CRC cells suffered a notable decline, which could be rescued by overexpressing KRT19. In addition, the proteasome inhibitor MG132 could block the degradation of KRT19 induced by DIAPH3 silencing. Conclusions Our study reveals that DIAPH3 mRNA was modified in CRC cells by m1A methylation. Silencing DIAPH3 suppresses the migration and invasion of CRC cells, potentially through the proteasome-dependent degradation of downstream KRT19.

show abstract

Section: Introductionmentioning

confidence: 79%

m1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

Mi,

Lou,

Chen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compounds 12 and 17 exhibited inhibitory activity against Clk2 with IC 50 values of 617 nM and 708 nM, as shown in Table 2 . Notably, the overexpression of Clk3 in colorectal cancer [ 55 ] and hepatocellular carcinoma [ 56 ] was previously highlighted. However, none of the tested compounds revealed any significant inhibitory activity against Clk3.…”

Section: Resultsmentioning

confidence: 99%

N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents

Mostafa,

Chen,

Darwish

et al. 2024

Cancers

View full text Add to dashboard Cite

Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

show abstract

“…The repressive impact of m 1 A on translation is probably due to its scarcity in cytosolic mRNAs [ 17 , 59 ]. For the m 1 A eraser genes ALKBH1 and ALKBH3, it was suggested that the mRNA expression of MFAP2 and the methylation modification of m 1 A were increased in colorectal cancer when ALKBH1 was silenced [ 60 ]. The depletion of ALKBH3 enhances the decay of Aurora A mRNA and inhibits its translation [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a N1-methyladenosine-related risk signature for breast carcinoma by bioinformatics analysis and experimental validation

Yang

Jia

et al. 2023

Breast Cancer

View full text Add to dashboard Cite

Objectives Breast carcinoma (BRCA) has resulted in a huge health burden globally. N1-methyladenosine (m1A) RNA methylation has been proven to play key roles in tumorigenesis. Nevertheless, the function of m1A RNA methylation-related genes in BRCA is indistinct. Methods The RNA sequencing (RNA-seq), copy-number variation (CNV), single-nucleotide variant (SNV), and clinical data of BRCA were acquired via The Cancer Genome Atlas (TCGA) database. In addition, the GSE20685 dataset, the external validation set, was acquired from the Gene Expression Omnibus (GEO) database. 10 m1A RNA methylation regulators were obtained from the previous literature, and further analyzed through differential expression analysis by rank-sum test, mutation by SNV data, and mutual correlation by Pearson Correlation Analysis. Furthermore, the differentially expressed m1A-related genes were selected through overlapping m1A-related module genes obtained by weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) in BRCA and DEGs between high- and low- m1A score subgroups. The m1A-related model genes in the risk signature were derived by univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. In addition, a nomogram was built through univariate and multivariate Cox analyses. After that, the immune infiltration between the high- and low-risk groups was investigated through ESTIMATE and CIBERSORT. Finally, the expression trends of model genes in clinical BRCA samples were further confirmed by quantitative real-time PCR (RT‒qPCR). Results Eighty-five differentially expressed m1A-related genes were obtained. Among them, six genes were selected as prognostic biomarkers to build the risk model. The validation results of the risk model showed that its prediction was reliable. In addition, Cox independent prognosis analysis revealed that age, risk score, and stage were independent prognostic factors for BRCA. Moreover, 13 types of immune cells were different between the high- and low-risk groups and the immune checkpoint molecules TIGIT, IDO1, LAG3, ICOS, PDCD1LG2, PDCD1, CD27, and CD274 were significantly different between the two risk groups. Ultimately, RT-qPCR results confirmed that the model genes MEOX1, COL17A1, FREM1, TNN, and SLIT3 were significantly up-regulated in BRCA tissues versus normal tissues. Conclusions An m1A RNA methylation regulator-related prognostic model was constructed, and a nomogram based on the prognostic model was constructed to provide a theoretical reference for individual counseling and clinical preventive intervention in BRCA.

show abstract

MFAP2, upregulated by m1A methylation, promotes colorectal cancer invasiveness via CLK3

Cited by 16 publications

References 28 publications

m1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

m1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents

Establishment of a N1-methyladenosine-related risk signature for breast carcinoma by bioinformatics analysis and experimental validation

Contact Info

Product

Resources

About