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. 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.

• Authors: 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
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 1 Pg. 89 (01 18 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33462212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KDM4C protein, human
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• TP53 protein, human
• Tumor Suppressor Protein p53
• Jumonji Domain-Containing Histone Demethylases
• Doxycycline

Topics

• Animals
• Brain Neoplasms (genetics, metabolism, pathology)
• Carcinogenesis
• Cell Line, Tumor
• Doxycycline (pharmacology)
• Epigenesis, Genetic
• Glioblastoma (genetics, metabolism, pathology)
• Heterografts
• Humans
• Jumonji Domain-Containing Histone Demethylases (genetics, metabolism)
• Mice
• Proto-Oncogene Proteins c-myc (genetics)
• Random Allocation
• Transfection
• Tumor Suppressor Protein p53 (genetics)