The role of deubiquitinating enzyme USP17 in non-small cell lung cancer as a potential therapeutic target

Abstract

The deubiquitinase USP17 is a ubiquitin specific protease which functions to cleave ubiquitin from its substrate proteins. USP17 has been shown to regulate cell cycle progression, lysosomal trafficking, and epithelial-to- mesenchymal transition (EMT), and its expression has been associated with cancer progression and reduced progression free survival. Depletion of USP17 is reported to reduce non-small cell lung cancer (NSCLC) tumourigenesis and enhance sensitivity to first line tyrosine-kinase inhibitors.

Chapter 3 investigates USP17’s impact on NSCLC growth in 3D in vitro studies, and the cellular impact of its phosphorylation at S41. USP17 expression increases A549 colony formation in 3D clonogenic assays, which is dependent on its deubiquitinating activity and phosphorylation at S41. Similarly, USP17 depletion reduces A549 colony formation. Additionally, USP17 drives EMT and protease secretion via lysosomal exocytosis in NSCLC, regardless of the phosphorylation status at S41.

Chapter 4 investigates USP17’s impact on gefitinib sensitivity of EGFR mutant (mtEGFR) NSCLC using 3D spheroid in vitro models. USP17 depletion in combination with gefitinib treatment led to a significant reduction of spheroid volume in of mtEGFR NSCLC lines H1975 and HCC827.

Chapter 5 investigates the protein interactome of USP17 using the BioID2 proximity dependent biotinylation system, identifying potential protein-protein interactions of USP17. Gene ontology analysis suggests that by interacting with its substrates, USP17 may be involved with the regulation of vesicular trafficking, GTPase activation, and cell migration.

Overall, the data in this thesis provides additional insight to the importance of USP17 in various NSCLC cellular processes, and further supports its potential as a NSCLC therapeutic target.

Thesis is embargoed until 31st December 2026.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	James Burrows (Supervisor) & Roberta Burden (Supervisor)