Targeting DNA binding proteins for cancer therapy

Abstract

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.

Transcription Factors BARX1 and DLX4 Contribute to Progression of Clear Cell Renal Cell Carcinoma via Promoting Proliferation and Epithelial–Mesenchymal Transition

“…Recent studies have elucidated that somatic mutations and chromosomal abnormality can cause and promote tumorigenesis and progression, in which TFs are considered as driver genes ( Dang, 2012 ; Yokoyama, 2017 ). In fact, developing inhibitors that can suppress the activity of dysregulated TFs has been a promising approach for tumor-targeted therapy ( Shiroma et al, 2020 ). Shiroma et al (2020) and Qian et al (2020) have reviewed the small-molecule selective inhibitors that target cancer-associated TFs in both blood tumors and solid tumors.…”

“…Regulation of transcription is complex, and transcription is finely regulated by multiple participants, including transcription factors (TFs) ( Yevshin et al, 2019 ). TFs account for ∼8% of all human genes, and they can regulate target gene expression through specific recognizing and binding to the corresponding promoter or enhancer region ( Lambert et al, 2018 ; Yevshin et al, 2019 ; Qian et al, 2020 ; Shiroma et al, 2020 ). Lambert et al (2018) systematically identified and functionally characterized 1,639 human TFs.…”

“… Lambert et al (2018) systematically identified and functionally characterized 1,639 human TFs. The dysregulation of TFs is associated with a wide array of diseases, including cancer ( Lambert et al, 2018 ; Shiroma et al, 2020 ). The amplification, deletion, point mutations, and epigenetic modification of transcription factor (TF) genes usually disorder gene expression networks, consequently resulting in the acquisition of tumor malignancies including cell over-proliferation, migration, invasion, drug resistance, immune evasion, metastasis, and immunosuppression ( Qian et al, 2020 ; Shiroma et al, 2020 ).…”

“…The dysregulation of TFs is associated with a wide array of diseases, including cancer ( Lambert et al, 2018 ; Shiroma et al, 2020 ). The amplification, deletion, point mutations, and epigenetic modification of transcription factor (TF) genes usually disorder gene expression networks, consequently resulting in the acquisition of tumor malignancies including cell over-proliferation, migration, invasion, drug resistance, immune evasion, metastasis, and immunosuppression ( Qian et al, 2020 ; Shiroma et al, 2020 ). For example, SOX2, DUX4, TRF1, and TRF2 were associated with the progression of breast cancer, melanoma, glioma, and colon cancer, respectively, ( Shiroma et al, 2020 ).…”

“…The amplification, deletion, point mutations, and epigenetic modification of transcription factor (TF) genes usually disorder gene expression networks, consequently resulting in the acquisition of tumor malignancies including cell over-proliferation, migration, invasion, drug resistance, immune evasion, metastasis, and immunosuppression ( Qian et al, 2020 ; Shiroma et al, 2020 ). For example, SOX2, DUX4, TRF1, and TRF2 were associated with the progression of breast cancer, melanoma, glioma, and colon cancer, respectively, ( Shiroma et al, 2020 ). There were also a large number of TFs involving in ccRCC, such as hypoxia-induced factor 1 alpha (HIF-1α) ( Schödel et al, 2016 ), hypoxia-induced factor 2 alpha ( Schödel et al, 2016 ), and ZNF395 ( Yao et al, 2017 ; Sun et al, 2020 ).…”