SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

Abstract

Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.

SOD2 acetylation and deacetylation: Another tale of Jekyll and Hyde in cancer

“…Thus, understanding how CSC function and survival are controlled is important. In PNAS, He et al (10) extend previous findings (11,12) and further establish a causal relationship between manganese superoxide dismutase (SOD2) overexpression and CSC formation, and provide a mechanism that explains this association involving acetylated SOD2, increased mitochondrial H 2 O 2 , and HIF2α expression.…”

“…Indeed, the peroxidase activity of SOD2 has been shown to increase oxidative damage to mitochondria and sensitize cells to peroxide stress (23,24). He et al (10) demonstrate that scavenging of H 2 O 2 prevented the increase in OCT4 and Nanog mRNA, as well as HIF2α and cancer stemness in SOD2-overexpressing cells. This sets up an interesting proposition whereby SOD2 K68 uses H 2 O 2 as a substrate for the peroxidase reaction, and somehow this leads to further H 2 O 2 generation that selects for surviving CSC-like cells and/or is key for reprogramming.…”

“…If SOD2 is an antioxidant, why does its overexpression not confer greater protection, but instead result in a flipping of its function to a procancer role? Insights into this conundrum are provided by He et al (10). They show that CSC gene expression signatures were greater in SOD2-overexpressing MCF7 cells (breast cancer-derived epithelial cells) compared to parental controls.…”

“…To determine how SOD2 overexpression could promote reprogramming toward a CSC-like state, He et al (10) focus on HIF2α as a critical downstream mediator. HIF2α, but not HIF1α, protein was increased in SOD2-overexpressing MCF-7 cells.…”

“…It will be interesting to determine whether there are synergistic effects under hypoxia, particularly for well-established hypoxia-induced phenotypes such as invasion and stem cell maintenance. Next, He et al (10) address how SOD2 overexpression results in elevation of HIF2α in relation to SOD2 catalytic activity. A compelling set of data indicate that SOD2-dependent induction of the CSC-like phenotype is not related to superoxide dismutation per se but a peroxidase activity that is associated with SOD2 acetylation.…”