Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc
Abstract Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. How...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03380-2 |
| _version_ | 1818456740987928576 |
|---|---|
| author | Dong Hoon Lee Go Woon Kim Jung Yoo Sang Wu Lee Yu Hyun Jeon So Yeon Kim Hyeok Gu Kang Da-Hyun Kim Kyung-Hee Chun Junjeong Choi So Hee Kwon |
| author_facet | Dong Hoon Lee Go Woon Kim Jung Yoo Sang Wu Lee Yu Hyun Jeon So Yeon Kim Hyeok Gu Kang Da-Hyun Kim Kyung-Hee Chun Junjeong Choi So Hee Kwon |
| author_sort | Dong Hoon Lee |
| collection | DOAJ |
| description | Abstract Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM4C’s roles in glioblastoma and the underlying molecular mechanisms remain unclear. Here, we show that KDM4C knockdown significantly represses proliferation and tumorigenesis of glioblastoma cells in vitro and in vivo that are rescued by overexpressing wild-type KDM4C but not a catalytic dead mutant. KDM4C protein expression is upregulated in glioblastoma, and its expression correlates with c-Myc expression. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. Importantly, KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53K372me1, which is pivotal for the stability of chromatin-bound p53. Conversely, depletion or inhibition of KDM4C promotes p53 target gene expression and induces apoptosis in glioblastoma. KDM4C may serve as an oncogene through the dual functions of inactivation of p53 and activation of c-Myc in glioblastoma. Our study demonstrates KDM4C inhibition as a promising therapeutic strategy for targeting glioblastoma. |
| first_indexed | 2024-12-14T22:31:29Z |
| format | Article |
| id | doaj.art-d0de556d57c8492ca33374883b95cc94 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-14T22:31:29Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d0de556d57c8492ca33374883b95cc942022-12-21T22:45:14ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111410.1038/s41419-020-03380-2Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-MycDong Hoon Lee0Go Woon Kim1Jung Yoo2Sang Wu Lee3Yu Hyun Jeon4So Yeon Kim5Hyeok Gu Kang6Da-Hyun Kim7Kyung-Hee Chun8Junjeong Choi9So Hee Kwon10College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityDepartment of Biochemistry and Molecular Biology, Yonsei University College of MedicineDepartment of Biochemistry and Molecular Biology, Yonsei University College of MedicineDepartment of Biochemistry and Molecular Biology, Yonsei University College of MedicineCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityAbstract Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM4C’s roles in glioblastoma and the underlying molecular mechanisms remain unclear. Here, we show that KDM4C knockdown significantly represses proliferation and tumorigenesis of glioblastoma cells in vitro and in vivo that are rescued by overexpressing wild-type KDM4C but not a catalytic dead mutant. KDM4C protein expression is upregulated in glioblastoma, and its expression correlates with c-Myc expression. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. Importantly, KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53K372me1, which is pivotal for the stability of chromatin-bound p53. Conversely, depletion or inhibition of KDM4C promotes p53 target gene expression and induces apoptosis in glioblastoma. KDM4C may serve as an oncogene through the dual functions of inactivation of p53 and activation of c-Myc in glioblastoma. Our study demonstrates KDM4C inhibition as a promising therapeutic strategy for targeting glioblastoma.https://doi.org/10.1038/s41419-020-03380-2 |
| spellingShingle | Dong Hoon Lee Go Woon Kim Jung Yoo Sang Wu Lee Yu Hyun Jeon So Yeon Kim Hyeok Gu Kang Da-Hyun Kim Kyung-Hee Chun Junjeong Choi So Hee Kwon Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc Cell Death and Disease |
| title | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
| title_full | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
| title_fullStr | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
| title_full_unstemmed | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
| title_short | Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc |
| title_sort | histone demethylase kdm4c controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c myc |
| url | https://doi.org/10.1038/s41419-020-03380-2 |
| work_keys_str_mv | AT donghoonlee histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT gowoonkim histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT jungyoo histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT sangwulee histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT yuhyunjeon histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT soyeonkim histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT hyeokgukang histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT dahyunkim histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT kyungheechun histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT junjeongchoi histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc AT soheekwon histonedemethylasekdm4ccontrolstumorigenesisofglioblastomabyepigeneticallyregulatingp53andcmyc |