RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade
Abstract MYC is one of the most commonly dysregulated proto-oncogenes in cancer. MYC promotes cancer initiation and maintenance by regulating multiple biological processes, such as proliferation and stem cell function. Here, we show that developmental regulator RUNX3 targets MYC protein for rapid de...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05037-0 |
| _version_ | 1797784496051847168 |
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| author | Vincent Oei Linda Shyue Huey Chuang Junichi Matsuo Supriya Srivastava Ming Teh Yoshiaki Ito |
| author_facet | Vincent Oei Linda Shyue Huey Chuang Junichi Matsuo Supriya Srivastava Ming Teh Yoshiaki Ito |
| author_sort | Vincent Oei |
| collection | DOAJ |
| description | Abstract MYC is one of the most commonly dysregulated proto-oncogenes in cancer. MYC promotes cancer initiation and maintenance by regulating multiple biological processes, such as proliferation and stem cell function. Here, we show that developmental regulator RUNX3 targets MYC protein for rapid degradation through the glycogen synthase kinase-3 beta-F-box/WD repeat-containing protein 7 (GSK3β-FBXW7) proteolytic pathway. The evolutionarily conserved Runt domain of RUNX3 interacts directly with the basic helix–loop–helix leucine zipper of MYC, resulting in the disruption of MYC/MAX and MYC/MIZ-1 interactions, enhanced GSK3β-mediated phosphorylation of MYC protein at threonine-58 and its subsequent degradation via the ubiquitin-proteasomal pathway. We therefore uncover a previously unknown mode of MYC destabilization by RUNX3 and provide an explanation as to why RUNX3 inhibits early-stage cancer development in gastrointestinal and lung mouse cancer models. |
| first_indexed | 2024-03-13T00:40:44Z |
| format | Article |
| id | doaj.art-81bc164fee3c44cba5df1af325e126bb |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-13T00:40:44Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-81bc164fee3c44cba5df1af325e126bb2023-07-09T11:21:45ZengNature PortfolioCommunications Biology2399-36422023-07-016111510.1038/s42003-023-05037-0RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascadeVincent Oei0Linda Shyue Huey Chuang1Junichi Matsuo2Supriya Srivastava3Ming Teh4Yoshiaki Ito5Cancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeDepartment of Medicine, National University of SingaporeDepartment of Pathology, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeAbstract MYC is one of the most commonly dysregulated proto-oncogenes in cancer. MYC promotes cancer initiation and maintenance by regulating multiple biological processes, such as proliferation and stem cell function. Here, we show that developmental regulator RUNX3 targets MYC protein for rapid degradation through the glycogen synthase kinase-3 beta-F-box/WD repeat-containing protein 7 (GSK3β-FBXW7) proteolytic pathway. The evolutionarily conserved Runt domain of RUNX3 interacts directly with the basic helix–loop–helix leucine zipper of MYC, resulting in the disruption of MYC/MAX and MYC/MIZ-1 interactions, enhanced GSK3β-mediated phosphorylation of MYC protein at threonine-58 and its subsequent degradation via the ubiquitin-proteasomal pathway. We therefore uncover a previously unknown mode of MYC destabilization by RUNX3 and provide an explanation as to why RUNX3 inhibits early-stage cancer development in gastrointestinal and lung mouse cancer models.https://doi.org/10.1038/s42003-023-05037-0 |
| spellingShingle | Vincent Oei Linda Shyue Huey Chuang Junichi Matsuo Supriya Srivastava Ming Teh Yoshiaki Ito RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade Communications Biology |
| title | RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade |
| title_full | RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade |
| title_fullStr | RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade |
| title_full_unstemmed | RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade |
| title_short | RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade |
| title_sort | runx3 inactivates oncogenic myc through disruption of myc max complex and subsequent recruitment of gsk3β fbxw7 cascade |
| url | https://doi.org/10.1038/s42003-023-05037-0 |
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