While loss of antioxidant expression and the resultant oxidant-dependent damage to cellular macromolecules is key to tumorigenesis, it has become evident that effective oxidant scavenging is conversely necessary for successful metastatic spread. This dichotomous role of antioxidant enzymes in cancer highlights their context-dependent regulation during different stages of tumor development. A prominent example of an antioxidant enzyme with such a dichotomous role and regulation is the mitochondria-localized manganese superoxide dismutase SOD2 (MnSOD). SOD2 has both tumor suppressive and promoting functions, which are primarily related to its role as a mitochondrial superoxide scavenger and H2O2 regulator. However, unlike true tumor suppressor- or onco-genes, the SOD2 gene is not frequently lost, or rarely mutated or amplified in cancer. This allows SOD2 to be either repressed or activated contingent on context-dependent stimuli, leading to its dichotomous function in cancer. Here, we describe some of the mechanisms that underlie SOD2 regulation in tumor cells. While much is known about the transcriptional regulation of the SOD2 gene, including downregulation by epigenetics and activation by stress response transcription factors, further research is required to understand the post-translational modifications that regulate SOD2 activity in cancer cells. Moreover, future work examining the spatio-temporal nature of SOD2 regulation in the context of changing tumor microenvironments is necessary to allows us to better design oxidant- or antioxidant-based therapeutic strategies that target the adaptable antioxidant repertoire of tumor cells.

https://www.mdpi.com/2076-3921/6/4/86/pdf

Insights into the Dichotomous Regulation of SOD2 in Cancer

Post-translational modification (PTM) in histone proteins is a covalent modification which mainly consists of methylation, phosphorylation, acetylation, ubiquitylation, SUMOylation, glycosylation, and ADP-ribosylation. PTMs have fundamental roles in chromatin structure and function. Histone modifications have also been known as epigenetic markers. The PTMs that have taken place in histone proteins can affect gene expression by altering chromatin structure. Histone modifications act in varied biological processes such as transcriptional activation/inactivation, chromosome packaging, mitosis, meiosis, apoptosis, and DNA damage/repair. Defects in the PTMs pathway have been associated with the occurrence and progression of various human diseases, such as cancer, heart failure, autoimmune diseases, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Histone modifications are reversible and used as potential targets for cancer therapy and prevention. Recent different histone PTMs have key roles in cancer cells since it has been shown that histone PTMs markers in cancers are acetylation, methylation, phosphorylation, and ubiquitylation. In this review, we have summarized the six most studied histone modifications and have examined the role of these modifications in the development of cancer.

Evaluation of post-translational modifications in histone proteins: A review on histone modification defects in developmental and neurological disorders

The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O2 •-) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O2 •-, and its by-product, peroxynitrite (ONOO-), which is generated by a reaction between O2 •- with nitric oxide (NO•), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction.

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease.

/pdf/hepatoma-derived-growth-factor-stimulates-cell-growth-after-1ekrnqpp04.pdf

Hepatoma-derived Growth Factor Stimulates Cell Growth after Translocation to The Nucleus by Nuclear Localization Signals

ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response.

Manganese superoxide dismutase (MNSOD) is one of the major scavengers of reactive oxygen species (ROS) in mitochondria with pivotal regulatory role in ischemic disorders, inflammation and cancer. Here we report oxidative modification of MNSOD in human renal cell carcinoma (RCC) by the shotgun method using data-dependent liquid chromatography tandem mass spectrometry (LC-MS/MS). While 5816 and 5571 proteins were identified in cancer and adjacent tissues, respectively, 208 proteins were found to be up- or down-regulated (p < 0.05). Ontological category, interaction network and Western blotting suggested a close correlation between RCC-mediated proteins and oxidoreductases such as MNSOD. Markedly, oxidative modifications of MNSOD were identified at histidine (H54 and H55), tyrosine (Y58), tryptophan (W147, W149, W205 and W210) and asparagine (N206 and N209) residues additional to methionine. These oxidative insults were located at three hotspots near the hydrophobic pocket of the manganese binding site, of which the oxidation of Y58, W147 and W149 was up-regulated around three folds and the oxidation of H54 and H55 was detected in the cancer tissues only (p < 0.05). When normalized to MNSOD expression levels, relative MNSOD enzymatic activity was decreased in cancer tissues, suggesting impairment of MNSOD enzymatic activity in kidney cancer due to modifications. Thus, LC-MS/MS analysis revealed multiple oxidative modifications of MNSOD at different amino acid residues that might mediate the regulation of the superoxide radicals, mitochondrial ROS scavenging and MNSOD activity in kidney cancer.

LC-MS/MS Analysis Unravels Deep Oxidation of Manganese Superoxide Dismutase in Kidney Cancer.

Histone acetylation adds an acetyl group on the lysine residue commonly found within the N-terminal tail protruding from the histone core of the nucleosome, and is important for chromosome structure and function in gene transcription and chromatin remodeling. Acetylation may also occur on other residues additional to lysine, but have not been thoroughly investigated at the proteomics level. Here we report a wide tolerance acetylation study mimicking the addition of 42 ± 0.5 Da delta mass modification on undefined amino acid residues of histones by shotgun proteomics using liquid chromatography–tandem mass spectrometry. A multi-blind spectral alignment algorithm with a wide peptide tolerance revealed frequent occurrence of 42 ± 0.5 Da modifications at lysine (K), serine (S) and threonine (T) residues in human histones from kidney tissues. Precision delta mass analysis identified acetylation (42.011 ± 0.004 Da) and trimethylation (42.047 ± 0.002 Da) modifications within the delta mass range. A specific antibody was produced to validate the acetylated T22 of human histone H3 (H3T22ac) by immune assays. Thus, we demonstrated that the wide tolerance acetylation approach identified histone acetylation as well as modification variants commonly associated with acetylation at undefined residues additional to lysine.

Post-Translational Modification of Human Histone by Wide Tolerance of Acetylation

ADAR1 is a double-stranded RNA (dsRNA) editing enzyme that specifically converts adenosine to inosine. ADAR1 is ubiquitously expressed in eukaryotes and participate in various cellular processes such as differentiation, proliferation and immune responses. We report here a new proteomics study of HEK293T cells with and without ADAR1 overexpression. The up- and down-regulated proteins by ADAR1 overexpression are identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by label-free protein quantification. Totally 1,495 proteins (FDR < 0.01) are identified, among which 211 are up- and 159 are down-regulated for at least 1.5-fold (n = 3, p < 0.05). Gene ontology analysis reveals that these ADAR1-regulated proteins are involved in protein translation and cell cycle regulation. Bioinformatics analysis identifies a closely related network consistent for the protein translation machinery and a tightly connected network through proliferating cell nuclear antigen (PCNA)-interactions....

https://www.tandfonline.com/doi/pdf/10.1080/15384101.2016.1176657

Unraveling molecular effects of ADAR1 overexpression in HEK293T cells by label-free quantitative proteomics.

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LC-MS/MS Analysis Unravels Deep Oxidation of Manganese Superoxide Dismutase in Kidney Cancer.

Post-Translational Modification of Human Histone by Wide Tolerance of Acetylation

Unraveling molecular effects of ADAR1 overexpression in HEK293T cells by label-free quantitative proteomics.