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.
Highlights
Autophagy promotes cancer cell survival in response to p53 activation by the anticancer agent Nutlin-3a (Nutlin)
We previously showed glycolysis and ␣-KG can protect cells against Nutlin-induced apoptosis by in some way maintaining expression of autophagy-related gene (ATG) genes required for autophagy [12, 17, 18]. ␣-KG is an intermediate metabolite of glucose and a cofactor for JMJD family histone lysine demethylases [19]
The results indicate H3K9me2/3 and H3K36me3 are increased in MDM2-amplified MHM and SJSA1 cells that are sensitive to Nutlin-induced apoptosis and either decreased or maintained in MDM2nonamplified A549 and U2OS cells that are resistant to this apoptosis [17]
Summary
JMJD2B knockdown or inhibition increased H3K9/K36me levels, decreased ATG gene expression and autophagy, and sensitized MDM2-nonamplified cells to apoptosis. We. JMJD2B regulates p53-mediated autophagy reported in MDM2-amplified cells that Nutlin treatment inhibits glucose metabolism and reduces ␣-ketoglutarate (␣-KG) levels and that this is critical for Nutlin-induced apoptosis [12, 17, 18]. We envisioned that JMJD2B could be induced by Nutlin-mediated activation of p53 and regulate histone methylation to affect ATG gene expression and autophagy. We found JMJD2B-mediated histone demethylation promotes ATG gene expression, autophagy, and survival in MDM2-nonamplified cells treated with Nutlin. The depletion of JMJD2B leads to increased histone methylation, reduced ATG gene expression and autophagy, and increased killing in MDM2-amplified cells
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