The histone demethylase JMJD2B is critical for p53-mediated autophagy and survival in Nutlin-treated cancer cells.

Abstract

Autophagy promotes cancer cell survival in response to p53 activation by the anticancer agent Nutlin-3a (Nutlin). We reported previously that Nutlin kills MDM2-amplified cancer cells and that this killing is associated with an inhibition of glucose metabolism, reduced α-ketoglutarate (α-KG) levels, and reduced autophagy. In the current report, using SJSA1, U2OS, A549, and MHM cells, we found that Nutlin alters histone methylation in an MDM2 proto-oncogene-dependent manner and that this, in turn, regulates autophagy-related gene (ATG) expression and cell death. In MDM2-amplified cells, Nutlin increased histone (H) 3 lysine (K) 9 and K36 trimethylation (me3) coincident with reduced autophagy and increased apoptosis. Blocking histone methylation restored autophagy and rescued these cells from Nutlin-induced killing. In MDM2-nonamplified cells, H3K9me3 and H3K36me3 levels were either reduced or not changed by the Nutlin treatment, and this coincided with increased autophagy and cell survival. Blocking histone demethylation reduced autophagy and sensitized these cells to Nutlin-induced killing. Further experiments suggested that MDM2 amplification increases histone methylation in Nutlin-treated cells by causing depletion of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B). Finally, JMJD2B knockdown or inhibition increased H3K9/K36me3 levels, decreased ATG gene expression and autophagy, and sensitized MDM2-nonamplified cells to apoptosis. Together, these results support a model in which MDM2- and JMJD2B-regulated histone methylation levels modulate ATG gene expression, autophagy, and cell fate in response to the MDM2 antagonist Nutlin-3a.

• Authors: Lei Duan, Ricardo E Perez, Xin Lai, Ling Chen, Carl G Maki
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 23 Pg. 9186-9197 (06 07 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 31036564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Duan et al.

Chemical References

• Autophagy-Related Proteins
• Histones
• Imidazoles
• MAS1 protein, human
• Piperazines
• Proto-Oncogene Mas
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• nutlin 3
• Jumonji Domain-Containing Histone Demethylases
• KDM4B protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Autophagy-Related Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Histones (metabolism)
• Humans
• Imidazoles (pharmacology)
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, genetics, metabolism)
• Methylation
• Piperazines (pharmacology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Tumor Suppressor Protein p53 (metabolism)