Ribavirin inhibits the growth and ascites formation of hepatocellular carcinoma through downregulation of type I CARM1 and type II PRMT5.

Type I co-activator-associated arginine methyltransferase 1 (CARM1) and type II protein arginine methyltransferase 5 (PRMT5) are highly expressed in multiple cancers including liver cancer and their overexpression contributes to poor prognosis, thus making them promising therapeutic targets. Here, we evaluated anti-tumor activity of ribavirin in hepatocellular carcinoma (HCC). We found that ribavirin significantly inhibited the proliferation of HCC cells in a time- and dose-dependent manner. Furthermore, ribavirin suppressed the growth of subcutaneous and orthotopic xenograft of HCC in mice, decreased vascular endothelial growth factor (VEGF) and peritoneal permeability to reduce ascites production, and prolonged the survival of mice in HCC ascites tumor models. Mechanistically, ribavirin potently down-regulated global protein expression of CARM1 and PRMT5, and concurrently decreased accumulation of H3R17me2a and H3R8me2s/H4R3me2s. However, ribavirin did not affect the activity and mRNA levels of both CARM1 and PRMT5 in vivo and in vitro HCC cells. In addition, our ChIP results shown that ribavirin inhibited CARM1 which in turn decreased the H3R17me2a, binds to the eukaryotic translation initiation factor 4E (eIF4E) and VEGF promoter region, and reduced the relative mRNA expression level of eIF4E and VEGF in HCC cells. Our findings suggested a potential therapeutic strategy for patients with HCC through inhibition of the abnormal activation/expression of both CARM1 and PRMT5.

Cell metabolic profiling of colorectal cancer via 1H NMR.

BACKGROUND: Protein arginine methyltransferase 5 (PRMT5) belongs to a large family of protein arginine methyltransferases (PRMTs) that play essential role in gene transcription and regulate tumorigenesis. However, the role of PRMT5 in the regulation of cancer cell metabolism remains unclear. METHODS: Cell metabolomic analysis was performed on SW480 cells transfected with small interfering RNA (siRNA) specifically targeting PRMT5, followed by metabolomic pathway analysis. RESULTS: PRMT5 was overexpressed in colorectal cancer (CRC) tissues, and downregulation of PRMT5 suppressed CRC cell proliferation and the levels of PRMT5 and symmetric dimethylation of histone H3 (H3R8me2s). In addition, we found distinct differences in metabolite classification and function in PRMT5 knockdown SW480 cells compared to control SW480 cells. PRMT5 knockdown increased the levels of amino acids and carbohydrates, particularly related to the arginine metabolism such as glutamate, glutamine (Gln), proline, creatine, creatinine and phosphocreatine (PCr). CONCLUSIONS: These findings revealed a key role for PRMT5 as a regulator of CRC cell metabolism to mediate arginine methylation in CRC cells.

Genome-wide identification and comparative analysis of drought-related microRNAs in two maize inbred lines with contrasting drought tolerance by deep sequencing.

Drought has become one of the most serious abiotic stresses influencing crop production worldwide. Understanding the molecular regulatory networks underlying drought adaption and tolerance in crops is of great importance for future breeding. microRNAs (miRNAs), as important components of post-transcriptional regulation, play crucial roles in drought response and adaptation in plants. Here, we report a miRNome analysis of two maize inbred lines with contrasting levels of drought tolerance under soil drought in the field. Differential expression analysis showed 11 and 34 miRNAs were uniquely responded to drought in H082183 (drought tolerant) and Lv28 (drought sensitive), respectively, in leaves. In roots, 19 and 23 miRNAs uniquely responded to drought in H082183 and Lv28, respectively. Expression analysis of these drought-responsive miRNA-mRNA modules revealed miR164-MYB, miR164-NAC, miR159-MYB, miR156-SPL and miR160-ARF showed a negative regulatory relationship. Further analysis showed that the miR164-MYB and miR164-NAC modules in the tolerant line modulated the stress response in an ABA (abscisic acid)-dependent manner, while the miR156-SPL and miR160-ARF modules in the sensitive line participated in the inhibition of metabolism in drought-exposed leaves. Together, our results provide new insight into not only drought-tolerance-related miRNA regulation networks in maize but also key miRNAs for further characterization and improvement of maize drought tolerance.

Genome-wide identification of gene expression in contrasting maize inbred lines under field drought conditions reveals the significance of transcription factors in drought tolerance.

Drought is a major threat to maize growth and production. Understanding the molecular regulation network of drought tolerance in maize is of great importance. In this study, two maize inbred lines with contrasting drought tolerance were tested in the field under natural soil drought and well-watered conditions. In addition, the transcriptomes of their leaves was analyzed by RNA-Seq. In total, 555 and 2,558 genes were detected to specifically respond to drought in the tolerant and the sensitive line, respectively, with a more positive regulation tendency in the tolerant genotype. Furthermore, 4,700, 4,748, 4,403 and 4,288 genes showed differential expression between the two lines under moderate drought, severe drought and their well-watered controls, respectively. Transcription factors were enriched in both genotypic differentially expressed genes and specifically responsive genes of the tolerant line. It was speculated that the genotype-specific response of 20 transcription factors in the tolerance line and the sustained genotypically differential expression of 22 transcription factors might enhance tolerance to drought in maize. Our results provide new insight into maize drought tolerance-related regulation systems and provide gene resources for subsequent studies and drought tolerance improvement.