Studies of DNA Tumor Viruses have been central to modern cancer research. Tumor viruses cause 10-15% of human cancers world-wide and have provided profound insights into both infectious and non-infectious cancer causes. Viral proteins tend to hijack central nodes of cellular networks, such as tumor suppressors p53 and RB, that are frequently mutated in non-viral cancers and likely to be the driver mutations. Therefore, studies of tumor virus oncoproteins and cancer genome sequencing have been two complementary approaches to increase the specificity of cancer gene identification.
Polyomaviruses are a family of 5 kb double-stranded circular DNA viruses. During the last decade, more than 10 new human polyomaviruses have been discovered. Several human polyomaviruses cause severe diseases. In particular, Merkel cell polyomavirus (MCV) causes the neuroendocrine skin cancer Merkel cell carcinoma (MCC). Virus negative MCC has also been discovered with many UV signature mutations. These two subtypes of MCC with different etiologies seem to converge on the same pathways and elicit nearly identical pathological phenotypes. To seek mechanism-based treatment for MCC, we recently determined that the MCV ST antigen recruits oncoprotein L-MYC to the Tip60-p400 complex, which functions as a powerful engine to transactivate gene expression and promote oncogenesis. By integrating ChIP-seq, RNA-seq and genome-scale CRISPR/Cas9 screens in MCC cells, we have identified several druggable targets downstream of the L-MYC and Tip60-p400 complex, such as PRMT5. Although neuroendocrine tumors occur in many different parts of the body, they are treated as a group of tissue due to common features. For example, MCC cells look very similar to small cell lung cancer (SCLC) cells and MCC has been treated akin to SCLC. The causal relationship between MCV and MCC provides a great tool to understand the biology of a group of cancers that start in neuroendocrine cells. The oncogenic activities of the Tip60-p400 complex identified in VP-MCC that is driven by L-MYC may also be further validated in cancers driven by oncoproteins c-MYC and N-MYC. MYC proteins are overexpressed in 50% of human cancers, e.g. L-MYC is often overexpressed in SCLC. MYC proteins are notoriously “undruggable” due to the lack of enzymatic activity or any deep pocket. Future cure for MYC-driven cancers rely on studies of MYC interacting epigenetic regulators or downstream effectors.
The lab is currently interested in identifying transforming proteins and oncogenes targeted by small DNA tumor viruses including polyomaviruses. We are particularly interested in the interplay between two MAX network components in Merkel cell carcinoma oncogenesis: the MCV ST, L-MYC and Tip60-p400 complex (SLaP) mediated transcriptional activation and the Polycomb Repressive Complex 1.6 (PRC1.6) mediated transcriptional repression. We are working on understanding how the m6A RNA methylation and PRMT5-mediated symmetric dimethylarginine (SDMA) formation on splicing factors safeguard proper splicing of proliferation-associated genes in cancer where MYC-driven global excess of pre-mRNA may overwhelm the splicing machinery.
* Highly motivated students are encouraged to apply for open spots in the lab. Please reach out to <a href="mailto:jingwei.cheng@unh.edu">jingwei.cheng@unh.edu</a>.
Courses Taught
- BCHM/BMCB 863/763: Biochemistry of Cancer
- BMS 706: Virology
- BMS 708: Virology Laboratory
- BMS 790: Undergrad Teaching Experience
- BMS/MICR 706/806: Virology
- BMS/MICR 708/808: Virology Laboratory
- INCO 590: Student Research Experience
- MCBS 999: Doctoral Research
Research Interests
- Epigenetics
- Gene Regulation
- Genome Structure/Function
- Omics Studies (Genomics, Proteomics, Metabolomics)
- Skin Cancer
- Transcription
- Viral Studies (Virology)
Selected Publications
Cheng, J., Park, D. E., Berrios, C., White, E. A., Arora, R., Yoon, R., . . . DeCaprio, J. A. (n.d.). Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis. PLOS Pathogens, 13(10), e1006668. doi:10.1371/journal.ppat.1006668
Cheng, J., Rozenblatt-Rosen, O., Paulson, K. G., Nghiem, P., & DeCaprio, J. A. (2013). Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities. Journal of Virology, 87(11), 6118-6126. doi:10.1128/jvi.00385-13
Cheng, J., DeCaprio, J. A., Fluck, M. M., & Schaffhausen, B. S. (2009). Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens. Seminars in Cancer Biology, 19(4), 218-228. doi:10.1016/j.semcancer.2009.03.002