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Project description:Protein Arginine Methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with its therapeutic potential demonstrated through synthetic lethality in MTAP-deleted cancers. Emerging evidence also suggests that MYC-driven or p53 wild-type tumors may be more sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma (MCC) serves as an ideal model to explore this question, as it is driven by the MYC paralog MYCL, and most virus-positive MCCs retain wild-type p53. In this study, we investigated PRMT5’s impact on the Tip60-EP400 complex, given MCC’s reliance on the interaction between MYCL and this complex. We used second-generation sequencing (Illumina) to characterize PRMT5-mediated bulk gene expression and long-read RNA sequencing (PacBio Iso-Seq) to analyze PRMT5-mediated alternative splicing. The mechanism underlying PRMT5 deficiency's selective impact on specific splice sites while leaving others unaffected remains unclear. Our findings suggest that PRMT5-mediated methylation of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper splicing of Tip60 and maintaining Tip60-EP400 activity. In contrast, PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including both exon skipping and intron retention. These results provide new insights into PRMT5’s role in splicing regulation in cancer cells and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.
2025-08-20 | GSE290105 | GEO
Project description:Protein Arginine Methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with its therapeutic potential demonstrated through synthetic lethality in MTAP-deleted cancers. Emerging evidence also suggests that MYC-driven or p53 wild-type tumors may be more sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma (MCC) serves as an ideal model to explore this question, as it is driven by the MYC paralog MYCL, and most virus-positive MCCs retain wild-type p53. In this study, we investigated PRMT5’s impact on the Tip60-EP400 complex, given MCC’s reliance on the interaction between MYCL and this complex. We used second-generation sequencing (Illumina) to characterize PRMT5-mediated bulk gene expression and long-read RNA sequencing (PacBio Iso-Seq) to analyze PRMT5-mediated alternative splicing. The mechanism underlying PRMT5 deficiency's selective impact on specific splice sites while leaving others unaffected remains unclear. Our findings suggest that PRMT5-mediated methylation of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper splicing of Tip60 and maintaining Tip60-EP400 activity. In contrast, PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including both exon skipping and intron retention. These results provide new insights into PRMT5’s role in splicing regulation in cancer cells and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.
2025-08-20 | GSE290569 | GEO
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion
| PRJNA1228975 | ENA
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [JNJvsDMSO_raw]
| PRJNA1226215 | ENA
Project description:PRMT5-mediated SRSF1 methylation promotes virus-positive Merkel cell carcinoma tumorigenesis by increasing Tip60 exon inclusion [PacBio Sequel IIe]
| PRJNA1228633 | ENA
Project description:PRMT1 is highly expressed in breast tumors, and has been suggested to play a vital role in breast tumorigenesis, but the underlying molecular mechanisms remain to be fully characterized. Here, we reveal that PRMT1 exhibits a wide-spreading role in RNA alternative splicing based on transcriptome analysis, with a preference for exon inclusion in a large cohort of oncogenic genes. Profiling PRMT1 methylome reveals that the arginine/serine-rich splicing factor SRSF1 is heavily arginine-methylated by PRMT1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and PRMT1-induced exon inclusion. In breast tumors, the overexpression of PRMT1 is associated with high levels of SRSF1 arginine methylation and aberrant exon inclusion in those oncogenic genes. Accordingly, PRMT1-mediated SRSF1 methylation and exon inclusion events are found to be critical for the malignant behaviors of breast cancer cells. Furthermore, we identified and characterized a selective PRMT1 inhibitor iPRMT1, which is potent in inhibiting PRMT1-mediated SRSF1 methylation and exon inclusion events, and breast cancer cell growth both in vitro and in vivo. Combination treatment with iPRMT1 and inhibitor targeting SRSF1 phosphorylation, SPHINX31 or SRPIN340, exhibits synergistic effects on suppressing breast cancer cell growth, strengthening the cross-talk between arginine methylation and phosphorylation in SRSF1. In conclusion, our data uncover a key mechanism underlying PRMT1-mediated gene alternative splicing, demonstrating targeting PRMT1 has great potential to treat breast cancer in clinic.
2023-10-02 | GSE212049 | GEO
Project description:Steroid receptor RNA activator 1 (SRA1) has been described as a novel transcriptional co-activator that affects the migration of cancer cells. Through RT-PCR, we identified that skipping exon 3 of SRA1 produces two isoforms, including the truncated short isoform, SRA1-S, and the long isoform, SRA1-L. However, the effect of these two isomers on the migration of HCC cells, as well as the specific mechanism of exon 3 skipping remain unclear. In this study, we found up regulated expression of SRSF1 and SRA1-L in highly metastatic HCCLM3, as well as in HCCs with SRSF1 demonstrating the strongest correlation with SRA1-L. In contrast, we observed a constitutively low expression of SRA1-S and SRSF1 in lowly metastatic HepG2 cells. Overexpression of SRSF1 or SRA1-L promoted migration and invasion by increasing the expression of CD44, while SRA1-S reversed the effect of SRSF1 and SRA1-L in vitro. In addition, lung metastasis in mice revealed that, knockdown of SRSF1 or SRA1-L inhibited the migration of HCC cells, while SRA1-L overexpression abolished the effect of SRSF1 knockout and instead promoted HCC cells migration in vivo. More importantly, RNA immunoprecipitation and Cross-link immunoprecipitation analyses showed that SRSF1 interacts with exon 3 of SRA1 to up regulate the expression of SRA1-L in HCC cells. RNA pull-down results indicated that SRSF1 could also bind to exon 3 of SRA1 in vitro. Finally, minigene -MS2 mutation experiments showed that mutation of the SRA1 exon 3 binding site for SRSF1 prevented the binding of SRA1 pre-mRNA. In summary, our results provide experimental evidence that SRA1 exon 3 inclusion is up regulated by SRSF1 to promote tumor invasion and metastasis in hepatocellular carcinoma.
| S-EPMC8134443 | biostudies-literature
Project description:Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.
| S-EPMC5451312 | biostudies-literature
Project description:Targeting PRMT1-mediated SRSF1 Methylation to Suppress Exon Inclusion within Oncogenic Transcripts and Breast Tumorigenesis
| PRJNA873704 | ENA
Project description:BackgroundMerkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC.MethodsIn this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a clinically implemented, next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome and software to detect integration sites and structure.ResultsSequencing from this approach revealed distinct integration junctions in the tumor genome and generated assemblies that strongly support a model of microhomology-initiated hybrid, virus-host, circular DNA intermediate that promotes focal amplification of host and viral DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Finally, comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival.ConclusionsThese results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of UV and viral oncogenesis in MCC. Furthermore, integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of MCC risk factors.
| S-EPMC7081548 | biostudies-literature