Phase Separation-involved Roles of Mediator Complex in Myc-amplified Cancer

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ABSTRACT High frequency of Myc gene amplification is found in many types of cancer, driving the oncogenic activity in cancer progression. Here I have noticed that the gene encoding one component of the transcription machinery mediator complex(MED) protein, MED30, is significantly co-amplified with Myc, and thus might complement the effects of enhanced Myc transcription activity. This correlation suggests a potentially useful adjunct therapeutic target in Myc-amplified cancer. MED contains thirty components and regulates gene expression by promoting assembly of the transcription preinitiation complex (PIC) and elongation. My preliminary data has revealed the unequal structural and functional importance of individual component of MED, by which MED30, located in Tail module, is required for assemble of at least the Tail and Middle MED modules, while, in contrast, another tail protein MED15 is not required. Mechanistically, 1,6-hexanediol-disrupted phase separation play a critical role in it. MED30 depletion leads to protein degradation of many other MED components, while MED15 does not. ChIP- seq reveals MED is widely enriched in enhancer and active transcribed gene promoters, and regulates target genes that represents a cancer-associated signature. MED works as a rapid transcription switch in response to extracellular signals. Therefore, I propose to rigorously test the molecular basis for MED30 function as one of the core components of MED, linked to cancer exhibiting Myc amplification, which will be the basis for competitive binding-based drug targeting, and screening for small molecules that can interrupt mediator complex by high affinity to MED30. I will further explore the molecular mechanism of MED involved transcription regulation in synergistic with Myc, and investigate the in vivo effect of MED30 inhibition in many cancers, including pancreatic cancer and a glioblastoma mouse model. This study will simultaneously extend our understanding of the potential cooperative component of Myc-induced cancer, investigate the roles of phase separation in these biological events, particularly on the aspect of protein stability regulation important for Mediator function, as well as how the cells tune their transcriptional program through enhanced MED30 and Myc TF transcription activity. I will focus on this overlooked and apparently common event in cancer biology, with the goal of providing new insights into transcription inhibitory drug development and protein degradation-oriented drug targeting strategies.