Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2).

Khushboo Sharma, Sanjeev Kumar Singh, Abhishek Kumar, Manmeet Kaur, Anushka Bhrdwaj, Anuraj Nayarisseri, Francisco Jaime Bezerra Mendonça Junior, Srinivas Bandaru, Arshiya Khan, Dipannita Ghosh, Ishita Chopra, Aravind Panicker, Priyadevi Saravanan, Pranoti Belapurkar

Journal: Advances in protein chemistry and structural biology 2024;141():223-253

PMID: 38960475

Full Text on Elsevier Science View on PubMed

Abstract

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.

Address: In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India; Bioinformatics Research Laboratory, LeGene Biosciences Pvt Ltd, Indore, Madhya Pradesh, India. Electronic address: [email protected].; In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India; Department of Biotechnology, Koneru Lakshmaiah Educational Foundation (KLEF), Green Fields, Vaddeswaram, Andhra Pradesh, India.; In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India; Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.; In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India.; In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India; School of Medicine and Health Sciences, The George Washington University, Washington, DC, United States.; In silico Research Laboratory, Eminent Biosciences, Indore, Madhya Pradesh, India; Department of Biosciences, Acropolis Institute, Indore, Madhya Pradesh, India.; Department of Biosciences, Acropolis Institute, Indore, Madhya Pradesh, India.; Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraiba, João Pessoa, Brazil.; Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.

DOI: 10.1016/bs.apcsb.2023.12.012