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.

KDM4C Promotes Proliferation and Migration of Multiple Myeloma Cells by Up-Regulating JAG1 Gene Expression

“…We found that silencing KDM4C suppressed the proliferation and migration ability of multiple myeloma cells. These results were consistent with the previous studies 6,20,21) . Lee et al found that down-regulation of KDM4C inhibited proliferation and tumorigenesis of glioblastoma cells 20) .…”

“…These results were consistent with the previous studies 6,20,21) . Lee et al found that down-regulation of KDM4C inhibited proliferation and tumorigenesis of glioblastoma cells 20) . Lin et al revealed that KDM4C knockdown suppressed proliferation and soft agar colony formation ability of prostate cancer cells 6) .…”

Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications

“…D609 suppressed ßFGF-stimulated astrocyte spread, probably due to SMS inhibition and an elevation in levels of ceramide [ 49 ]. By inhibiting SMS and upregulating the cyclin-dependent kinase (Cdk) inhibitors p27 and p21, D609 can cause the cell-cycle arrest and increase ceramide levels [ 50 , 51 , 52 ]. Ceramide may stimulate p27 and p21 expression by activating c-myc regulating protein phosphatase 2A (PP2A), which suppresses p21 and p27 expression [ 53 ].…”

Gene Transactivation and Transrepression in MYC-Driven Cancers

“…Ciclopirox targets KDM4B, inhibiting MYC signaling pathways and tumor growth in MYC-driven neuroblastomas [158]. SD70, a KDM4C-selective inhibitor, represses MYC transcription and activates p53, inducing apoptosis in glioblastoma [159].…”