Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

T.S. Karin Eisinger

Abstract

Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most aggressive and lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal muscle UPS cells and tissues, enforcing a myoblast-like identity. Importantly, differentiation is contingent upon downregulation of the Hippo pathway transcriptional effector, Yes-activated protein 1 (YAP1) and its downstream effectors in the NF-κB pathway. YAP1 and NF-κB are critical mediators of myoblast proliferation and their activity must be down regulated to permit differentiation. Previously, we observed that Vorinostat/JQ1 suppresses YAP1 and NF-κB activity and as a result, inhibits tumorigenesis, and promotes differentiation. Here I show that YAP1 and NF-B activity suppress circadian clock function, inhibiting differentiation and promoting unchecked proliferation. In most tissues clock activation is antagonized by the unfolded protein response (UPR). However, skeletal muscle differentiation requires both Clock and UPR, suggesting the molecular link between them is unique in muscle. In skeletal muscle-derived UPS we observed that YAP1 suppresses PERK and ATF6-mediated UPR target expression as well as clock genes. These pathways govern metabolic processes including autophagy and their disruption supports a shift in metabolism toward cancer cell-associated glycolysis and hyper-proliferation. Treatment with Vorinostat/JQ1 successfully inhibited glycolysis/MTOR signaling, activated the clock, and upregulated the UPR and autophagy via YAP1. These findings support the use of epigenetic modulators to treat human UPS and define the connection between these pathways and their effects on tissue differentiation. Additionally, we identify specific metabolic and differentiation genes as potential biomarkers of treatment efficacy.

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