Kazutake Tsujikawa
The field of epitranscriptomics, an area of genetics concerning the regulation of gene expression via post-transcriptional RNA modification, is currently attracting substantial research attention. In epitranscriptomics, proteins, collectively termed writers, erasers, and readers, enter into complex interactions that contribute to modifying RNA, thereby maintaining biological homeostasis. However, abnormalities in the expression or function of these proteins can lead to the onset and progression of cancers and neuropsychiatric disorders. Using prostate cancer clinical specimens, I cloned a novel gene, prostate cancer antigen-1 (PCA-1), containing a domain similar to the 2-oxoglutarate, iron(II) [Fe(II)]-dependent oxygenase domain of the Escherichia coli AlkB protein and characterized by enzymatic activity associated with the demethylation of methylated RNA. This was accordingly designated AlkB homolog 3 (ALKBH3). I demonstrate that ALKBH3 is highly expressed in tumor cells in prostate, pancreatic, lung, and other cancers, and its activity is correlated with a poor prognosis. In addition, I developed novel compounds that inhibit the RNA demethylase activity of ALKBH3, thereby providing a basis for developing a first-in-class cancer therapeutic. I also succeeded in cloning the ALKBH8 gene. High ALKBH8 expression was also observed in bladder cancer cells. Furthermore, abnormalities in development and behavior were noted in the generated Alkbh8 knockout mice. On the basis of the experience gained from ALKBH3 drug discovery research, I have established a foundation system for supporting academic drug discovery research. In this review, I describe the pathway followed in integrating the findings of basic pharmaceutical and drug discovery research and further developments.