SMYD3 Promotes Cell Cycle Progression by Inducing Cyclin D3 Transcription and Stabilizing the Cyclin D1 Protein in Medulloblastoma.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Maximum safe resection, postoperative craniospinal irradiation, and chemotherapy are the standard of care for MB patients. MB is classified into four subgroups: Shh, Wnt, Group 3, and Group 4. Of these subgroups, patients with Myc+ Group 3 MB have the worst prognosis, necessitating alternative therapies. There is increasing interest in targeting epigenetic modifiers for treating pediatric cancers, including MB. Using an RNAi functional genomic screen, we identified the lysine methyltransferase SMYD3, as a crucial epigenetic regulator that drives the growth of Group 3 Myc+ MB cells. We demonstrated that SMYD3 directly binds to the cyclin D3 promoter to activate its transcription. Further, SMYD3 depletion significantly reduced MB cell proliferation and led to the downregulation of cyclin D3, cyclin D1, pRBSer795, with concomitant upregulations in RB in vitro. Similar results were obtained following pharmacological inhibition of SMYD3 using BCI-121 ex vivo. SMYD3 knockdown also promoted cyclin D1 ubiquitination, indicating that SMYD3 plays a vital role in stabilizing the cyclin D1 protein. Collectively, our studies demonstrate that SMYD3 drives cell cycle progression in Group 3 Myc+ MB cells and that targeting SMYD3 has the potential to improve clinical outcomes for high-risk patients.

Pathogenic Role of Epstein-Barr Virus in Lung Cancers.

Human oncogenic viruses account for at least 12% of total cancer cases worldwide. Epstein-Barr virus (EBV) is the first identified human oncogenic virus and it alone causes ~200,000 cancer cases and ~1.8% of total cancer-related death annually. Over the past 40 years, increasing lines of evidence have supported a causal link between EBV infection and a subgroup of lung cancers (LCs). In this article, we review the current understanding of the EBV-LC association and the etiological role of EBV in lung carcinogenesis. We also discuss the clinical impact of the knowledge gained from previous research, challenges, and future directions in this field. Given the high clinical relevance of EBV-LC association, there is an urgent need for further investigation on this topic.

Role of Virally Encoded Circular RNAs in the Pathogenicity of Human Oncogenic Viruses.

Human oncogenic viruses are a group of important pathogens that etiologically contribute to at least 12% of total cancer cases in the world. As an emerging class of non-linear regulatory RNA molecules, circular RNAs (circRNAs) have gained increasing attention as a crucial player in the regulation of signaling pathways involved in viral infection and oncogenesis. With the assistance of current circRNA enrichment and detection technologies, numerous novel virally-encoded circRNAs (vcircRNAs) have been identified in the human oncogenic viruses, initiating an exciting new era of vcircRNA research. In this review, we discuss the current understanding of the roles of vcircRNAs in the respective viral infection cycles and in virus-associated pathogenesis.

Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis.

Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC+ MB's. Evidence for a direct transcriptional role of MYC on the B7-H3 gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs.