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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.

Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. Such exchange results in tumor‐educated platelets with altered RNA expression profiles. Multiple lines of evidence indicate that platelet RNA profiles may be suitable as diagnostic biomarkers for cancer‐related biological processes. In this study, we characterized the gene expression signatures of platelets in breast cancer (BC) by high‐throughput sequencing and quantitative real‐time RT‐PCR. Our results indicate that the expression of TPM3 (tropomyosin 3) mRNA is significantly elevated in platelets from patients with BC compared with age‐matched healthy control subjects. Furthermore, up‐regulation of TPM3 mRNA in platelets was found to be significantly correlated with metastasis in patients with BC. Finally, we report that platelet TPM3 mRNA is delivered into BC cells through microvesicles and leads to enhanced migrative phenotype of BC cells. In summary, our findings suggest that the transfer of platelet TPM3 mRNA into cancer cells via microvesicles promotes cancer cell migration, and thus platelet‐derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic BC., Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. In this study, we found that platelet TPM3 (tropomyosin 3) mRNA can be delivered into cancer cells via microvesicles to promote cancer cell migration. Platelet‐derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic breast cancer.

Human globin gene expression during development is modulated by transcription factors in a stage-dependent manner. However, the mechanisms controlling the process are still largely unknown. In this study, we found that a nuclear protein, LYAR (human homologue of mouse Ly-1 antibody reactive clone) directly interacted with the methyltransferase PRMT5 which triggers the histone H4 Arg3 symmetric dimethylation (H4R3me2s) mark. We found that PRMT5 binding on the proximal γ-promoter was LYAR-dependent. The LYAR DNA-binding motif (GGTTAT) was identified by performing CASTing (cyclic amplification and selection of targets) experiments. Results of EMSA and ChIP assays confirmed that LYAR bound to a DNA region corresponding to the 5′-untranslated region of the γ-globin gene. We also found that LYAR repressed human fetal globin gene expression in both K562 cells and primary human adult erythroid progenitor cells. Thus, these data indicate that LYAR acts as a novel transcription factor that binds the γ-globin gene, and is essential for silencing the γ-globin gene.