Date of Award
Spring 4-3-2023
Embargo Period
4-3-2025
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Department
Biochemistry
Additional Department
Pediatrics
College
College of Graduate Studies
Additional College
College of Medicine
First Advisor
Denis C. Guttridge
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue cancer among
children, characterized by a skeletal muscle lineage that is impaired from
undergoing terminal differentiation. NF-κB is constitutively active in cancer cells
and plays a critical role in cell survival. Although NF-κB is also activated in RMS,
surprisingly we find that these tumors are less dependent on NF-κB to overcome
stress-induced cell death. Instead, RMS cells survive by being partially
differentiated under the control of the myogenic transcription factor MyoD. Loss of
MyoD or cellular reprogramming dedifferentiates RMS tumor cells and promotes
cell death when exposed to stress. Further, use of a CRISPR screen identified the
tumor suppressor gene, CYLD, controlled by MyoD mediated DNA
methyltransferase activity to regulate RMS survival. Together, results reveal
oncogenic functions of MyoD that enhance RMS survival through pro-differentiation
and anti-cell death activities; findings that challenge the long existing
paradigm of MyoD in RMS pathogenesis.
Recommended Citation
Oles, Alexander, "MyoD Functions as an Oncogene in Rhabdomyosarcoma by Promoting Survival Through Differentiation and CYLD" (2023). MUSC Theses and Dissertations. 778.
https://medica-musc.researchcommons.org/theses/778
Rights
Copyright is held by the author. All rights reserved.
Included in
Medical Cell Biology Commons, Medical Molecular Biology Commons, Musculoskeletal, Neural, and Ocular Physiology Commons