Yoshitomo Shiroma and Ryou-u Takahashi contributed equally to this work.Abbreviations: AEP, AF4 family/ENL family/P-TEFb; ARNT, aryl hydrocarbon receptor nuclear translocator; BRD4, bromodomain-containing protein 4; CBP, CREB-binding protein; DUX4, double homeobox protein 4; ETO, eight-twenty one; EWS, Ewing's sarcoma; FLI1, friend leukemia virus integration 1; HIF, hypoxia-inducible factor; MLL, mixed-lineage leukemia; SOX2, Sry-related high-mobility box 2; STAT3, signal transducer and activator of transcription 3; TF, transcription factor; TRF, telomere-repeat binding factor. AbstractDysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs. K E Y W O R D SDNA binding protein, drug discovery, high-throughput screening, telomere, transcription factor | 1059 SHIROMA et Al.

The telomere G‐tail (G‐tail) plays an essential role in maintaining chromosome stability. In this study, we assessed the leukocyte G‐tail length of breast cancer (BC) patients and cancer‐free individuals and evaluated the association between the G‐tail length and the presence of BC. A significant shortening of the median G‐tail length was observed in BC patients compared with cancer‐free individuals and was found in the early phase of BC. Our study indicated that the leukocyte G‐tail length might be a potential biomarker for BC detection.

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Nuclear factor-κB (NF-κB) is an important transcription factor involved in various biological functions, including tumorigenesis. Hence, NF-κB has attracted attention as a target factor for cancer treatment, leading to the development of several inhibitors. However, existing NF-κB inhibitors do not discriminate between its subunits, namely, RelA, RelB, cRel, p50, and p52. Conventional methods used to evaluate interactions between transcription factors and DNA, such as electrophoretic mobility shift assay and luciferase assays, are unsuitable for high-throughput screening (HTS) and cannot distinguish NF-κB subunits. We developed a HTS method named DNA strand exchange fluorescence resonance energy transfer (DSE-FRET). This assay is suitable for HTS and can discriminate a NF-κB subunit. Using DSE-FRET, we searched for RelA-specific inhibitors and verified RelA inhibition for 32,955 compounds. The compound A55 (2-(3-carbamoyl-6-hydroxy-4-methyl-2-oxopyridin-1(2H)-yl) acetic acid) selectively inhibited RelA–DNA binding. We propose that A55 is a seed compound for RelA-specific inhibition and could be used in clinical applications.

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