The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma
Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hy...
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| Language: | English |
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Wiley
2022-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/7945884 |
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| author | Si-Qi Jia Ran Zhuo Zi-Mu Zhang Yang Yang Yan-Fang Tao Jian-Wei Wang Xiao-Lu Li Yi Xie Gen Li Di Wu Yan-Ling Chen Juan-Juan Yu Chen-xi Feng Zhi-Heng Li Rong-Fang Zhou Ran-Dong Yang Peng-Cheng Yang Bi Zhou Xiao-Mei Wan Yu-Meng Wu Wan-Yan Jiao Ni-Na Zhou Fang Fang Jian Pan |
| author_facet | Si-Qi Jia Ran Zhuo Zi-Mu Zhang Yang Yang Yan-Fang Tao Jian-Wei Wang Xiao-Lu Li Yi Xie Gen Li Di Wu Yan-Ling Chen Juan-Juan Yu Chen-xi Feng Zhi-Heng Li Rong-Fang Zhou Ran-Dong Yang Peng-Cheng Yang Bi Zhou Xiao-Mei Wan Yu-Meng Wu Wan-Yan Jiao Ni-Na Zhou Fang Fang Jian Pan |
| author_sort | Si-Qi Jia |
| collection | DOAJ |
| description | Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB. |
| format | Article |
| id | doaj-art-e42b467cdd344ef6a7ec6c79f6e4847d |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
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| series | Journal of Immunology Research |
| spelling | doaj-art-e42b467cdd344ef6a7ec6c79f6e4847d2025-08-20T03:26:25ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/7945884The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in NeuroblastomaSi-Qi Jia0Ran Zhuo1Zi-Mu Zhang2Yang Yang3Yan-Fang Tao4Jian-Wei Wang5Xiao-Lu Li6Yi Xie7Gen Li8Di Wu9Yan-Ling Chen10Juan-Juan Yu11Chen-xi Feng12Zhi-Heng Li13Rong-Fang Zhou14Ran-Dong Yang15Peng-Cheng Yang16Bi Zhou17Xiao-Mei Wan18Yu-Meng Wu19Wan-Yan Jiao20Ni-Na Zhou21Fang Fang22Jian Pan23Institute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchNeuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.http://dx.doi.org/10.1155/2022/7945884 |
| spellingShingle | Si-Qi Jia Ran Zhuo Zi-Mu Zhang Yang Yang Yan-Fang Tao Jian-Wei Wang Xiao-Lu Li Yi Xie Gen Li Di Wu Yan-Ling Chen Juan-Juan Yu Chen-xi Feng Zhi-Heng Li Rong-Fang Zhou Ran-Dong Yang Peng-Cheng Yang Bi Zhou Xiao-Mei Wan Yu-Meng Wu Wan-Yan Jiao Ni-Na Zhou Fang Fang Jian Pan The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma Journal of Immunology Research |
| title | The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma |
| title_full | The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma |
| title_fullStr | The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma |
| title_full_unstemmed | The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma |
| title_short | The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma |
| title_sort | brd4 inhibitor dbet57 exerts anticancer effects by targeting superenhancer related genes in neuroblastoma |
| url | http://dx.doi.org/10.1155/2022/7945884 |
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