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PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression
- Source :
- Theranostics
- Publication Year :
- 2020
- Publisher :
- Ivyspring International Publisher, 2020.
-
Abstract
- The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18INK4C), CDKN1A (p21CIP1/WAF1), CDKN1C (p57KIP2) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer.
- Subjects :
- 0301 basic medicine
Protein-Arginine N-Methyltransferases
Gene Expression
Medicine (miscellaneous)
Adenocarcinoma
medicine.disease_cause
Methylation
Proto-Oncogene Mas
Histones
Proto-Oncogene Proteins c-myc
Histone H4
03 medical and health sciences
0302 clinical medicine
Stomach Neoplasms
Histone arginine methylation
Cell Line, Tumor
Gene expression
medicine
Humans
PTEN
Promoter Regions, Genetic
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
biology
gastric cancer
Protein arginine methyltransferase 5
Promoter
histone arginine methylation
Gene Expression Regulation, Neoplastic
tumorigenesis
c-Myc
030104 developmental biology
030220 oncology & carcinogenesis
Disease Progression
biology.protein
Cancer research
PRMT5
Carcinogenesis
Chromatin immunoprecipitation
Research Paper
Subjects
Details
- ISSN :
- 18387640
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....8911a0411921bd02734d0908cc01e2e4