About this Research Topic
Glutathione S-transferases (GSTs), composed of at least eight classes of isoenzymes, are important phase II detoxifying enzymes and are vital for maintaining cellular homeostasis. GST’s overexpression and nuclear localization in some instances have been shown to correlate with drug resistance as well as with advanced tumor stage and aggressiveness. In contrast, silencing of GST genes through promoter methylation is a frequent event in many cancers. Moreover, some GSTs null genotypes have been related to an increased risk for some types of cancers. Regardless of the importance of GST activity for cellular vitality, the GST gene cluster is a hotspot for DNA sequence mutations that leads to the expression of active but functionally different GST variant proteins. Mechanistically, single nucleotide polymorphisms leading to amino acid substitution might influence the detoxification activities of GST enzymes and predispose individuals to various cancers. Interestingly, GSTs can also interact with other proteins and some of these interactions block apoptosis and favor cellular transformation.
A systematic study of common genetic variation in the GST genes and their haplotypes, as well as characterization of the functional significance of that variation, should contribute to mechanistic and epidemiologic studies of the involvement of GSTs in carcinogenesis, as well as individual variation in response to antineoplastic drug therapy.
Recently, several GST-inhibitors and prodrugs were proposed as crucial agents that can reverse multidrug resistance in tumors and increase the therapeutic index of anticancer drugs. However, further drug development is challenged by a large number of GST family members, with each subtype having its own structural and functional differences. The situation is further compounded by the presence of posttranslational modifying factors, such as kinase activities and S-glutathionylation. More in-depth research is needed to clarify the role of each of these components in the GST-detoxification system.
In summary, GSTs have advanced beyond the classic view of their role in metabolism and are prompting scientists to systematically evaluate their value for cancer risk characterization and drug resistance and to explore possibilities in overcoming resistance in relation to the modification of GST functions.
This Research Topic welcomes Original Research, Brief Research Report, Review articles, and new ideas related, but not limited, to the following topics:
• GST gene family analysis, synthesis, localization, and cellular function in relation to cancer
• Genetic susceptibility including GST genes polymorphism and their role in cancer
• Genetic variations in GST genes and their functional significance in cancer
• Regulation of GST expression at an epigenetic level including DNA methylation and histone modification
• Role of small regulatory RNAs in modulating GST activity
• GSTs as cancer biomarkers
• Role of GSTs in overcoming anti-cancer drug resistance
• Role of GSTs in regulating cellular metabolism during cancer
• GSTs, oxidative stress, and cancer
• Effect of GST-inhibitors and prodrugs on GST-related pathways
Topic Editor Birendranath Banerjee is a founder and the Managing Director of inDNA Life Sciences Pvt Ltd. All other topic editors declare no competing interests with regards to the Research Topic subject.
Keywords: Glutathione S-transferase, GST polymorphisms, Tumor resistance, GST inhibitors, protein-protein interaction, pro-drugs
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