Publication Date

2015-08-07

Availability

Open access

Embargo Period

2015-08-07

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2015-07-29

First Committee Member

David J. Robbins

Second Committee Member

Anthony J. Capobianco

Third Committee Member

Murray P. Deutscher

Fourth Committee Member

Dao M. Nguyen

Fifth Committee Member

Grace R. Zhai

Abstract

Two major biological questions regarding Hedgehog (HH) signaling were investigated in this dissertation. The first important question is the role of lipid modification in HH ligand function, while the second one is epigenetic regulation in HH-driven cancer. In the second chapter, identification of lipid modifications in HH ligands from different contexts and pertinent functional studies were performed to elaborate the role of lipids in regulating the biological properties of HH. This is the first description of heterogeneous fatty acylation in a fully processed form of HH ligand, and shows that such a profile of lipidation is dynamic in different cellular contexts. These lipid speciated HH ligands were shown to exhibit distinct potency and intracellular trafficking. In the third chapter, an unbiased epigenetic compound screen was performed to identify compounds that attenuate HH-driven luciferase activity. One of these compounds was a bromodomain and extra terminal (BET) protein inhibitor. This inhibitor potently inhibited HH signaling in vitro and in vivo. Mechanistic studies demonstrated that it acted downstream of SMO, mutations of which have led to resistance to an FDA-approved drug currently being used in the clinic. Targeting BET proteins may bypass this mutation-induced drug resistance when treating HH-driven cancer.

Keywords

Sonic Hedgehog; Lipid Speciation; Epigenetic Modulation; HH-driven Cancer

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