Histone Demethylase Jumonji D3 (JMJD3) as a Tumor Suppressor by Regulating p53 Protein Nuclear Stabilization

Abstract

Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation.

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

“…KDM6B can directly associate with key transcription factors, such as p53 (67,68), p65, and p50 NF-KB subunits (37) and STAT (69,70) and SMAD (71) family members, enhancing their functions. In turn, a reciprocal mode of regulation Table 3.…”

DNA Methylation-mediated Repression of miR-941 Enhances Lysine (K)-specific Demethylase 6B Expression in Hepatoma Cells

“…However, the genetic lesion is rather poorly correlated with mutations in TP53 (35). Deregulation of JMJD3 may contribute to gliomagenesis by inhibiting the p53 pathway with obstruction by terminal differentiation (37). Thus, KDM6B may be a tumor suppressor gene.…”

Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases

“…KDM4A promotes cellular transformation through transcriptional repression of the tumor suppressor CHD5 (69), and KDM6B has been found to promote the epithelial-mesenchymal transition (70). Conversely, others have demonstrated that KDM6B acts as a tumor suppressor by regulating p53 nuclear stabilization (71). In colorectal cancer, depletion of KDM5B induced cellular senescence (72).…”