One of the fundamental observations in oncology is that the rate of cancer malignancy increases with age, which applies to most human malignancies including breast cancer. Therefore, it is crucial to elucidate the mechanistic connection between aging and carcinogenesis. The NAD+-dependent sirtuin family, specifically SIRT3, the primary mitochondrial deacetylase, which was initially found to play a role in longevity and aging, appears to function as tumor suppressor proteins. SIRT3 regulates the enzymatic activities of multiple downstream substrates through balancing their deacetylation/acetylation status. In this dissertation, we studied the biological and physiological function of two critical SIRT3 lysine targets, lysine 68 (K68) in manganese superoxide dismutase (MnSOD) and lysine 635 (K635) in acetyl-coA synthetase 1 (ACSS1). We showed that upon acetylation, MnSOD-K68 led to the formation of monomeric structure, promoted a tumor-permissive phenotype in breast cancer cell lines, altered mitochondrial morphology/ultrastructure/metabolism, and gained an iron-incorporated peroxidase activity. We also introduced a novel ACSS1-K635Q mutation mouse model to mimic constitutive acetylation of ACSS1 in vivo. It was discovered that homozygous ACSS1-K635Q mice displayed lipid accumulation, dysregulated bioenergetics under fasting conditions and reduced mammary tumor burden. Taken together, this study expanded our knowledge on the functional role of protein acetylation as a critical post-translational modification and its potential as therapeutic targets in various disease models.

Creator

• Gao, Yucheng

DOI

• https://doi.org/10.21985/n2-paf3-vz17

Subject

• Biology

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15526
• etdadmin_upload_815100

Keyword

• MnSOD
• mitochondria
• Sirtuin
• cancer
• ACSS1
• metabolism

Date created

• 2021-01-01

Resource type

• Dissertation

Rights statement

• In Copyright