Date of Graduation
12-2012
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Mong-Hong Lee
Committee Member
Dr. Sai-Ching Yeung
Committee Member
Dr. Honami Naora
Committee Member
Dr. Peng Huang
Committee Member
Dr. Hui-Kuan Lin
Abstract
Metabolic reprogramming has been shown to be a major cancer hallmark providing tumor cells with significant advantages for survival, proliferation, growth, metastasis and resistance against anti-cancer therapies. Glycolysis, glutaminolysis and mitochondrial biogenesis are among the most essential cancer metabolic alterations because these pathways provide cancer cells with not only energy but also crucial metabolites to support large-scale biosynthesis, rapid proliferation and tumorigenesis. In this study, we find that 14-3-3σ suppresses all these three metabolic processes by promoting the degradation of their main driver, c-Myc. In fact, 14-3-3s significantly enhances c-Myc poly-ubiquitination and subsequent degradation, reduces c-Myc transcriptional activity, and down-regulates c-Myc-induced metabolic target genes expression. Therefore, 14-3-3σ remarkably blocks glycolysis, decreases glutaminolysis and diminishes mitochondrial mass of cancer cells both in vitro and in vivo, thereby severely suppressing cancer bioenergetics and metabolism. As a result, a high level of 14-3-3σ in tumors is strongly associated with increased breast cancer patients’ overall and metastasis-free survival as well as better clinical outcomes. Thus, this study reveals a new role for 14-3-3s as a significant regulator of cancer bioenergetics and a promising target for the development of anti-cancer metabolism therapies.
Keywords
cancer metabolism, metabolic reprogramming, regulation, 14-3-3sigma, p53, c-Myc, glycolysis, glutaminolysis, mitochondrial biogenesis, cancer
Included in
Biochemistry Commons, Bioinformatics Commons, Biology Commons, Cancer Biology Commons, Medicine and Health Sciences Commons, Molecular Biology Commons