Mitochondria are multifunctional cellular organelles that are major producers of reactive oxygen species (ROS) in eukaryotes; to maintain the redox balance, they are supplemented with different ROS scavengers, including mitochondrial peroxiredoxins (Prdxs). Mitochondrial Prdxs have physiological and pathological significance and are associated with the initiation and progression of various cancer types. In this review, we have focused on signaling involving ROS and mitochondrial Prdxs that is associated with cancer development and progression. An upregulated expression of Prdx3 and Prdx5 has been reported in different cancer types, such as breast, ovarian, endometrial, and lung cancers, as well as in Hodgkin’s lymphoma and hepatocellular carcinoma. The expression of Prdx3 and Prdx5 in different types of malignancies involves their association with different factors, such as transcription factors, micro RNAs, tumor suppressors, response elements, and oncogenic genes. The microenvironment of mitochondrial Prdxs plays an important role in cancer development, as cancerous cells are equipped with a high level of antioxidants to overcome excessive ROS production. However, an increased production of Prdx3 and Prdx5 is associated with the development of chemoresistance in certain types of cancers and it leads to further complications in cancer treatment. Understanding the interplay between mitochondrial Prdxs and ROS in carcinogenesis can be useful in the development of anticancer drugs with better proficiency and decreased resistance. However, more targeted studies are required for exploring the tumor microenvironment in association with mitochondrial Prdxs to improve the existing cancer therapies and drug development.

The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo O-GlcNAcylation modification. Thus, we further focused on elucidating how the regulation of O-linked β-N-acetylglucosamine (O-GlcNAc) modification is associated with the progression of hepatic steatosis leading to hepatitis in MCD diet mice. In parallel with lipid accumulation and inflammation, the MCD diet significantly up-regulated hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) via ER stress. Curcumin treatment alleviates the severity of hepatic steatosis by relieving the dependence of O-GlcNAcylation on nuclear factor-κB (NF-κB) in inflammation signaling. Conversely, the expressions of superoxide dismutase 1 (SOD1) and SIRT1 were significantly upregulated by curcumin treatment. In conclusion, curcumin inhibits O-GlcNAcylation pathway, leading to antioxidant responses in non-alcoholic steatohepatitis (NASH) mice. Therefore, curcumin will be a promising therapeutic agent for diseases involving hyper-O-GlcNAcylation, including cancer.

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally. NAFLD-which can develop into liver fibrosis, nonalcoholic steatohepatosis, cirrhosis, and hepatocellular carcinoma-is defined as an excess accumulation of fat caused by abnormal lipid metabolism and excessive reactive oxygen species (ROS) generation in hepatocytes. Recently, we reported that Peroxiredoxin 5 (Prx5) plays an essential role in regulating adipogenesis and suggested the need to further investigation on the potential curative effects of Prx5 on obesity-induced fatty liver disease. In the present study, we focused on the role of Prx5 in fatty liver disease. We found that Prx5 overexpression significantly suppressed cytosolic and mitochondrial ROS generation. Additionally, Prx5 regulated the AMP-activated protein kinase pathway and lipogenic gene (sterol regulatory element binding protein-1 and FAS) expression; it also inhibited lipid accumulation, resulting in the amelioration of free fatty acid-induced hepatic steatosis. Silence of Prx5 triggered de novo lipogenesis and abnormal lipid accumulation in HepG2 cells. Concordantly, Prx5 knockout mice exhibited a high susceptibility to obesity-induced hepatic steatosis. Liver sections of Prx5-deletion mice fed on a high-fat diet displayed Oil Red O-stained dots and small leaky shapes due to immoderate fat deposition. Collectively, our findings suggest that Prx5 functions as a protective regulator in fatty liver disease and that it may be a valuable therapeutic target for the management of obesity-related metabolic diseases.

Inji Park, and Hyun-Shik Lee. Mol. Cells 2015;38:14-9. https://doi.org/10.14348/molcells.2015.2116

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs.