BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia
Background. AML (acute myeloid leukemia) is a common hematological malignancy in children with poor treatment effects and poor prognosis. Recent studies have shown that as a novel BRD4 (bromodomain containing 4) PROTACs (proteolysis targeting chimeras) degrader, GNE-987 can slow down the growth of v...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
|
| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/7912484 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832565672050163712 |
|---|---|
| author | Xu Sang Yongping Zhang Fang Fang Li Gao Yanfang Tao Xiaolu Li Zimu Zhang Jianwei Wang Yuanyuan Tian Zhiheng Li Di Yao Yumeng Wu Xinran Chu Kunlong Zhang Li Ma Lihui Lu Yanling Chen Juanjuan Yu Ran Zhuo Shuiyan Wu Zhen Zhang Jian Pan Shaoyan Hu |
| author_facet | Xu Sang Yongping Zhang Fang Fang Li Gao Yanfang Tao Xiaolu Li Zimu Zhang Jianwei Wang Yuanyuan Tian Zhiheng Li Di Yao Yumeng Wu Xinran Chu Kunlong Zhang Li Ma Lihui Lu Yanling Chen Juanjuan Yu Ran Zhuo Shuiyan Wu Zhen Zhang Jian Pan Shaoyan Hu |
| author_sort | Xu Sang |
| collection | DOAJ |
| description | Background. AML (acute myeloid leukemia) is a common hematological malignancy in children with poor treatment effects and poor prognosis. Recent studies have shown that as a novel BRD4 (bromodomain containing 4) PROTACs (proteolysis targeting chimeras) degrader, GNE-987 can slow down the growth of various tumors and increase apoptosis, with promising clinical prospects. However, the function and molecular mechanism of GNE-987 in AML remain unclear. This study is aimed at investigating the therapeutic effect of GNE-987 on AML and its underlying mechanism. Methods. The association between BRD4 and AML was assessed by studying public databases. After GNE-987 was added to AML cells, cell proliferation slowed down, the cycle was disturbed, and apoptosis increased. Western blotting was used to detect BRD2 (bromodomain containing 2), BRD3 (bromodomain containing 3), BRD4, and PARP (poly ADP-ribose polymerase) proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq (RNA sequencing) and ChIP-seq (chromatin immunoprecipitation sequencing) validated the function and molecular pathways of GNE-987 in processing AML. Results. BRD4 expression was significantly elevated in pediatric AML samples compared with healthy donors. GNE-987 inhibited AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3, and BRD4 were consistent with decreased VHL (Von Hippel Lindau) expression in AML cells. In an AML xenograft model, GNE-987 significantly reduced the hepatosplenic infiltration of leukemia cells and increased the mouse survival time. Based on analysis of RNA-seq and ChIP-seq analyses, GNE-987 could target multiple SE- (super-enhancer-) related genes, including LYL1 (lymphoblastic leukemia 1), to inhibit AML. Conclusions. GNE-987 had strong antitumor activity in AML. GNE-987 could effectively inhibit the expression of SE-related oncogenes including LYL1 in AML. Our results suggested that GNE-987 had broad prospects in the treatment of AML. |
| format | Article |
| id | doaj-art-c117855d1fc2475a906024a6f1104a0f |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-c117855d1fc2475a906024a6f1104a0f2025-02-03T01:06:57ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/7912484BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid LeukemiaXu Sang0Yongping Zhang1Fang Fang2Li Gao3Yanfang Tao4Xiaolu Li5Zimu Zhang6Jianwei Wang7Yuanyuan Tian8Zhiheng Li9Di Yao10Yumeng Wu11Xinran Chu12Kunlong Zhang13Li Ma14Lihui Lu15Yanling Chen16Juanjuan Yu17Ran Zhuo18Shuiyan Wu19Zhen Zhang20Jian Pan21Shaoyan Hu22Department of HematologyDepartment of HematologyInstitute of Pediatric ResearchDepartment of HematologyInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchDepartment of HematologyInstitute of Pediatric ResearchDepartment of HematologyDepartment of HematologyDepartment of HematologyDepartment of HematologyDepartment of HematologyDepartment of HematologyInstitute of Pediatric ResearchInstitute of Pediatric ResearchInstitute of Pediatric ResearchIntensive Care UnitDepartment of PediatricsInstitute of Pediatric ResearchDepartment of HematologyBackground. AML (acute myeloid leukemia) is a common hematological malignancy in children with poor treatment effects and poor prognosis. Recent studies have shown that as a novel BRD4 (bromodomain containing 4) PROTACs (proteolysis targeting chimeras) degrader, GNE-987 can slow down the growth of various tumors and increase apoptosis, with promising clinical prospects. However, the function and molecular mechanism of GNE-987 in AML remain unclear. This study is aimed at investigating the therapeutic effect of GNE-987 on AML and its underlying mechanism. Methods. The association between BRD4 and AML was assessed by studying public databases. After GNE-987 was added to AML cells, cell proliferation slowed down, the cycle was disturbed, and apoptosis increased. Western blotting was used to detect BRD2 (bromodomain containing 2), BRD3 (bromodomain containing 3), BRD4, and PARP (poly ADP-ribose polymerase) proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq (RNA sequencing) and ChIP-seq (chromatin immunoprecipitation sequencing) validated the function and molecular pathways of GNE-987 in processing AML. Results. BRD4 expression was significantly elevated in pediatric AML samples compared with healthy donors. GNE-987 inhibited AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3, and BRD4 were consistent with decreased VHL (Von Hippel Lindau) expression in AML cells. In an AML xenograft model, GNE-987 significantly reduced the hepatosplenic infiltration of leukemia cells and increased the mouse survival time. Based on analysis of RNA-seq and ChIP-seq analyses, GNE-987 could target multiple SE- (super-enhancer-) related genes, including LYL1 (lymphoblastic leukemia 1), to inhibit AML. Conclusions. GNE-987 had strong antitumor activity in AML. GNE-987 could effectively inhibit the expression of SE-related oncogenes including LYL1 in AML. Our results suggested that GNE-987 had broad prospects in the treatment of AML.http://dx.doi.org/10.1155/2022/7912484 |
| spellingShingle | Xu Sang Yongping Zhang Fang Fang Li Gao Yanfang Tao Xiaolu Li Zimu Zhang Jianwei Wang Yuanyuan Tian Zhiheng Li Di Yao Yumeng Wu Xinran Chu Kunlong Zhang Li Ma Lihui Lu Yanling Chen Juanjuan Yu Ran Zhuo Shuiyan Wu Zhen Zhang Jian Pan Shaoyan Hu BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia Journal of Immunology Research |
| title | BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia |
| title_full | BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia |
| title_fullStr | BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia |
| title_full_unstemmed | BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia |
| title_short | BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia |
| title_sort | brd4 inhibitor gne 987 exerts anticancer effects by targeting super enhancer related gene lyl1 in acute myeloid leukemia |
| url | http://dx.doi.org/10.1155/2022/7912484 |
| work_keys_str_mv | AT xusang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT yongpingzhang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT fangfang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT ligao brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT yanfangtao brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT xiaoluli brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT zimuzhang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT jianweiwang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT yuanyuantian brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT zhihengli brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT diyao brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT yumengwu brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT xinranchu brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT kunlongzhang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT lima brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT lihuilu brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT yanlingchen brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT juanjuanyu brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT ranzhuo brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT shuiyanwu brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT zhenzhang brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT jianpan brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia AT shaoyanhu brd4inhibitorgne987exertsanticancereffectsbytargetingsuperenhancerrelatedgenelyl1inacutemyeloidleukemia |