Merkel Cell Polyomavirus Oncogenes Generate Targetable Synthetic Lethality
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CitationPark, Donglim. 2019. Merkel Cell Polyomavirus Oncogenes Generate Targetable Synthetic Lethality. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractViral oncogenes perturb cellular processes to ensure robust replication and this inadvertently creates synthetic lethality, or aberrant dependence on specific pathways. The goal of my research is to discover targetable synthetic lethality created by Merkel cell polyomavirus (MCV) in Merkel cell carcinoma (MCC) and other cancers.
MCC is an aggressive neuroendocrine cancer of the skin. Approximately 80% of MCC harbors the MCV genome and expresses large (LT) and small T (ST) antigens. While the MCV LT can inhibit RB, it does not bind p53. MCV LT binding to RB in fact leads to increased levels of ARF, an inhibitor of a major p53 degrading E3 ligase MDM2, and activation of p53. MCV ST recruits MYCL to the EP400 chromatin remodeler complex to transactivate specific genes. Through RNA- and ChIP-seq analysis, it was revealed that ST activates expression of MDM2 and CK1α, an activator of MDM4. Targeted degradation of CK1α by lenalidomide, deletion of CK1α, or a specific MDM4 inhibitor acted synergistically with MDM2 inhibitors to induce apoptosis in virus-positive MCC cells in vitro as well as xenografts in vivo, confirming the hypothesis that the combination of LT activating p53 and ST activating MDM2 and CK1α create MCC dependence on the MDM2-MDM4-CK1α pathway to override p53.
Investigation of ST regulation of gene expression revealed that ST specifically activates expression of several components of the LSD1 repressor complex. Inhibition of LSD1 activity reduces growth of MCV-positive MCC and suppresses ST’s transforming capacity in vitro and in vivo. Through a forward-genetic CRISPR-Cas9 screen, we identified an antagonistic relationship between LSD1 and the non-canonical BAF (ncBAF) chromatin remodeling complex. LSD1 inhibition could be partially rescued by BRD9 inhibition, revealing that LSD1 and ncBAF antagonistically regulate an overlapping set of genes.
My research investigating the role of MCV T antigens has uncovered the mechanism behind MCV control of p53 and provided insights into LSD1 synthetic lethality in MCC and the role of ncBAF as a novel tumor suppressor in cancer.
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