Histone demethylase inhibitors and theirpotential in prostate cancer treatment

Introduction: The gene encoding lysine demethylase ۳A [KDM۳A]belongs to the Jumonji C family of histone demethylasesand controls the expression of target genes by epigenetic regulationof histone ۳ methylation marks. This gene is dysregulatedin various types of cancer. It induces prostate cancer growth andprogression and leads to resistance of cancer cells to treatment.Identification of the mechanisms of the activity of the KDM۳Agene in prostate cancer tumorigenesis and its correlation withthe KDM۳A gene could provide insight into the effective treatmentof the disease.Materials and Methods: In a systematic review, using the keywordsof the JMJD۱A; histone demethylase and prostate cancerwere searched in PubMed and Google Scholar, and Scopus databasesand Related articles were reviewed.Result: Many inhibitors of demethylases have been identified,but these drugs are challenging because the catalytic sites ofthe enzymes are not only homologous to each other, but alsoto ۲-OG-dependent oxidases such as PHD۱ and FIH. The mainclasses of demethylase inhibitors include cofactor mimetics,substrate mimetics, and compounds whose mechanism of actionis not well defined. A number of researchers have used thedependence of JmjC family demethylases on ۲-OG to designinhibitors. Due to the structural similarity of these demethylasesto N-methyl demethylases and RNA demethylases, as well asnucleic acid oxygenases, inhibitors of ۲-OG oxygenases, suchas hydroxamate derivatives, N-oxalyl amino acid derivatives,pyridine, and dicarboxylate can also be used. It also proved tobe an effective inhibitor of demethylase activity in vitro and invivo, preferring KDM۴C over KDM۶A.Conclusion: KDM۳A plays a key role in promoting the progressionand treatment resistance of prostate cancer and is considereda promising target for the potential treatment of thiscancer. The success of histone demethylase inhibitors in reducingthe growth of prostate cancer cells points to the potential ofdeveloping these molecules for clinical users, and these studiespromise the successful application of this strategy.

کلیدواژه ها:

JMJD۱A ، KDM۳A ، epigenetics ، histone demethylase ، oncogene ، prostate cancer