Dataset Information

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-low Induction of Therapy Resistance

ABSTRACT: Genomic and transcriptomic alterations are insufficient to explain the variance in protein expression seen in cancer. Recent evidence has highlighted the role of N6-methyladenosine (m6A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post-transcriptional regulation mediated by m6A in cancer. Here we explore prostate cancer as an exemplar cancer and generate the first prostate m6A maps, and further examined how low levels of N6-adenosine-methyltransferase (METTL3) associates with advanced prostate cancer and results in altered expression at the level of transcription, translation, and protein. In particular extracellular matrix proteins have a high number of m6A sites and show significant changes in expression with METTL3 knock-down. We also discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knock-down rendered the cells resistant to androgen receptor antagonists, implicating changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Cancer Cell Line

DISEASE(S): Prostate Cancer

SUBMITTER: Manfred Heller

LAB HEAD: Mark Rubin

PROVIDER: PXD022348 | Pride | 2021-06-07

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	20191119_M3_Sh1_rep1_KC_i01.raw	Raw
	20191119_M3_Sh1_rep1_KC_i02.raw	Raw
	20191119_M3_Sh3_rep2_KC_i01.raw	Raw
	20191119_M3_Sh3_rep2_KC_i02.raw	Raw
	20191120_GFP_rep3_KC_i01.raw	Raw

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Publications

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.

Cotter Kellie A KA Gallon John J Uebersax Nadine N Rubin Philip P Meyer Kate D KD Piscuoglio Salvatore S Jaffrey Samie R SR Rubin Mark A MA

Molecular cancer research : MCR 20210604 8

Recent evidence has highlighted the role of N 6-methyladenosine (m6A) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by m6A in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of N 6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To investigate this relationship, we ...[more]

PMID: 34088870

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Project description:METTL3-mediated RNA N6-methyladenosine (m6A) is the most prevalent modification participates in tumor initiation and progression via regulating expression of their target genes in cancers. However, its role in tumor cell metabolism remains poorly appreciated. In this study, we conducted a multi-omics analysis including m6A microarray and quantitative proteomics to explore the potential effect and mechanism of METTL3 on the metabolism in gastric cancer cells. Our results found that significant alterations in the protein and m6A modification profile which induced by METTL3 overexpression in GC cells. Gene Ontology (GO) enrichment results showed that down-regulated proteins were significantly enriched in intracellular mitochondrial oxidative phosphorylation (OXPHOS), and the Protein-Protein Interaction (PPI) network analysis found that these differentially expressed proteins were significantly associated with OXPHOS. Subsequently, a prognostic model constructed based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the high-risk group showed a worse prognosis in GC patients. Meanwhile, the Gene Set Enrichment Analysis (GSEA) showed a significant enrichment in the energy metabolism signaling pathway. Then, combined with the results of the m6A microarray analysis, the intersection molecules of DEPs and differential methylation genes (DMGs) were significantly correlated with the genes involved in OXPHOS. Besides, there were also significant differences in prognosis and GSEA enrichment between the two clusters of GC patients classified according to consensus clustering algorithm. Finally, we focused on highly expressed, highly methylated molecules regulated by METTL3 and identified three (AVEN, DAZAP2, DNAJB1) genes that were significantly associated with poor prognosis in patients with GC. These results indicated that METTL3-regulated DEPs in GC cells were significantly associated with OXPHOS. After combined with m6A microarray analysis, the results suggested that these proteins might be involved in cell energy metabolism through m6A modifications thus influencing the prognosis of GC patients. Overall, our study revealed that METTL3 involved in cell metabolism through an m6A-dependent mechanism in GC cells, and indicated a potential biomarker for prognostic prediction in GC.

Dataset Information

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-low Induction of Therapy Resistance

Dataset's files

Publications

Mapping of m<sup>6</sup>A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-low Induction of Therapy Resistance

Dataset's files

Publications

Mapping of m&lt;sup&gt;6&lt;/sup&gt;A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Mapping of m<sup>6</sup>A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.