Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype

Abstract

Significance: Breast cancer is the most common nondermatologic malignancy among women in the United States, among which endocrine receptor-positive breast cancer accounts for up to 80%. Endocrine receptor-positive breast cancers can be categorized molecularly into luminal A and B subtypes, of which the latter is an aggressive form that is less responsive to endocrine therapy with inferior prognosis.

Recent advances: Sirtuin, an aging-related gene involved in mitochondrial metabolism, is associated with life span, and more importantly, murine models lacking Sirt3 spontaneously develop tumors that resemble human luminal B breast cancer. Furthermore, these tumors exhibit aberrant manganese superoxide dismutase (MnSOD) acetylation at lysine 68 and lysine 122 and have abnormally high reactive oxygen species (ROS) levels, which have been observed in many types of breast cancer.

Critical issues: The mechanism of how luminal B breast cancer develops resistance to endocrine therapy remains unclear. MnSOD, a primary mitochondrial detoxification enzyme, functions by scavenging excessive ROS from the mitochondria and maintaining mitochondrial and cellular homeostasis. Sirt3, a mitochondrial fidelity protein, can regulate the activity of MnSOD through deacetylation. In this study, we discuss a possible mechanism of how loss of SIRT3-guided MnSOD acetylation results in endocrine therapy resistance of human luminal B breast cancer.

Future directions: Acetylation of MnSOD and other mitochondrial proteins, due to loss of SIRT3, may explain the connection between ROS and development of luminal B breast cancer and how luminal B breast cancer becomes resistant to endocrine therapy. Antioxid. Redox Signal. 25, 326-336.

FIG. 1.

Cancer incidence increases with age. The incidence rate of human solid tumors increases exponentially after patients are older than 40 years. The shape of the curve is initially flat, and the inflection point occurs when the age reaches 40, with the curve being exponential after the inflection point.

FIG. 2.

Survival rates of Caenorhabditis elegans decrease with age and can be affected by sirtuins. This graph summarizes how the lifespan C. elegans changes as a function of age. The probability of survival starts with a flat slope, followed by an inflection point at around 2 weeks and a downward steep slope, indicating a decrease of survival rate as a function of age. Caloric restriction and/or enforced expression of sirtuins can shift the inflection point to the right, increasing C. elegans life span, whereas loss of sirtuins can shift the inflection point to the left, decreasing C. elegans life span. The shape of the survival curve remains unchanged, but the time of the inflection points can be shifted by the levels of sirtuins.

FIG. 3.

Proposed model of how dysregulation of circadian clock and SIRT3 activity can affect MnSOD detoxification and tumor-permissive phenotypes. Circadian clock has been shown to regulate NAD⁺ levels and NAD⁺-dependent SIRT3 activity. Dysregulation of circadian clock, on the other hand, results in a decrease in SIRT3 activity, which can affect energy metabolism in cells. In addition, MnSOD can be hyperacetylated at lysines 68 and 122 due to a decrease in SIRT3 activity. The dysregulation of energy metabolism and MnSOD activity can negatively affect cellular detoxification functions, resulting in an increase in ROS levels and tumor-permissive phenotypes. MnSOD, manganese superoxide dismutase; NAD⁺, nicotinamide adenine dinucleotide; ROS, reactive oxygen species.

FIG. 4.

Functions of SIRT3 in energy metabolism. SIRT3, in addition to its role as a mitochondrial NAD⁺-dependent protein deacetylase, can sense nutrient availability and reprogram mitochondrial nutrient production to match energy demands in nutrient consumption.

FIG. 5.

Proposed model of how SIRT3 deacetylation of MnSOD at lysine 122 can affect its activity. In this model, loss of SIRT3 activity (left) induces MnSOD hyperacetylation at lysine 122 and results in a neutral charge in the electrostatic funnel. Therefore, O₂^•− is repelled from the MnSOD activation site and cannot be converted to H₂O₂. Active SIRT3 (right), on the other hand, can deacetylate MnSOD at lysine 122, resulting in a positive charge in the electrostatic funnel. Therefore, more O₂^•− is attracted into the active site and converted to H₂O₂, facilitating MnSOD detoxification functions. H₂O₂, hydrogen peroxide.

FIG. 6.

Schema outline of how SIRT3 inhibits the Warburg effect, reduces ROS production, and prevents carcinogenesis. SIRT3 activates mitochondrial proteins involved in the TCA cycle (PDHA1 and IDH2) and electron transport chain (ATP synthase) through protein deacetylation, inhibiting the Warburg effect. In addition, SIRT3 can decrease ROS production in mitochondria by deacetylating MnSOD, which can activate its ROS detoxification functions. The production of aberrantly high levels of ROS, together with the Warburg effect, is thought to contribute to breast cancer carcinogenesis and endocrine resistance in breast cancer. ATP, adenosine triphosphate; IDH, isocitrate dehydrogenase; PDHA1, pyruvate dehydrogenase alpha 1; TCA, tricarboxylic acid cycle.