Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells
The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to t...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-11-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558619303240 |
| _version_ | 1828303127727570944 |
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| author | C. Otto S. Schmidt C. Kastner S. Denk J. Kettler N. Müller C.T. Germer E. Wolf P. Gallant A. Wiegering |
| author_facet | C. Otto S. Schmidt C. Kastner S. Denk J. Kettler N. Müller C.T. Germer E. Wolf P. Gallant A. Wiegering |
| author_sort | C. Otto |
| collection | DOAJ |
| description | The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1. |
| first_indexed | 2024-04-13T13:47:12Z |
| format | Article |
| id | doaj.art-d3ad9943a1bc4db391441e2d19b014f5 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-04-13T13:47:12Z |
| publishDate | 2019-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-d3ad9943a1bc4db391441e2d19b014f52022-12-22T02:44:26ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862019-11-01211111101120Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cellsC. Otto0S. Schmidt1C. Kastner2S. Denk3J. Kettler4N. Müller5C.T. Germer6E. Wolf7P. Gallant8A. Wiegering9Experimental Visceral Surgery, Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany; Corresponding authors at: Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany (A. Wiegering).University of Würzburg, Department of Biochemistry and Molecular Biology, Biocenter, Würzburg, GermanyUniversity of Würzburg, Department of Biochemistry and Molecular Biology, Biocenter, Würzburg, Germany; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, GermanyUniversity of Würzburg, Department of Biochemistry and Molecular Biology, Biocenter, Würzburg, GermanyExperimental Visceral Surgery, Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, GermanyInstitute for Virology and Immunobiology, University of Würzburg, Würzburg, GermanyDepartment of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany; University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, GermanyUniversity of Würzburg, Department of Biochemistry and Molecular Biology, Biocenter, Würzburg, GermanyUniversity of Würzburg, Department of Biochemistry and Molecular Biology, Biocenter, Würzburg, GermanyUniversity of Würzburg, Department of Biochemistry and Molecular Biology, Biocenter, Würzburg, Germany; Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital Würzburg, Germany; University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany; Corresponding authors at: Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery (Department of Surgery I), University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080 Würzburg, Germany (A. Wiegering).The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.http://www.sciencedirect.com/science/article/pii/S1476558619303240 |
| spellingShingle | C. Otto S. Schmidt C. Kastner S. Denk J. Kettler N. Müller C.T. Germer E. Wolf P. Gallant A. Wiegering Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells Neoplasia: An International Journal for Oncology Research |
| title | Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells |
| title_full | Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells |
| title_fullStr | Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells |
| title_full_unstemmed | Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells |
| title_short | Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells |
| title_sort | targeting bromodomain containing protein 4 brd4 inhibits myc expression in colorectal cancer cells |
| url | http://www.sciencedirect.com/science/article/pii/S1476558619303240 |
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