The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death

PLoS One. 2015 Jan 6;10(1):e0116782. doi: 10.1371/journal.pone.0116782. eCollection 2015.

Abstract

Transcription regulation emerged to be one of the key mechanisms in regulating autophagy. Inhibitors of H3K9 methylation activates the expression of LC3B, as well as other autophagy-related genes, and promotes autophagy process. However, the detailed mechanisms of autophagy regulated by nuclear factors remain elusive. In this study, we performed a drug screen of SMYD2-/- cells and discovered that SMYD2 deficiency enhanced the cell death induced by BIX01294, an inhibitor of histone H3K9 methylation. BIX-01294 induces accumulation of LC3 II and autophagy-related cell death, but not caspase-dependent apoptosis. We profiled the global gene expression pattern after treatment with BIX-01294, in comparison with rapamycin. BIX-01294 selectively activates the downstream genes of p53 signaling, such as p21 and DOR, but not PUMA, a typical p53 target gene inducing apoptosis. BIX-01294 also induces other autophagy-related genes, such as ATG4A and ATG9A. SMYD2 is a methyltransferase for p53 and regulates its transcription activity. Its deficiency enhances the BIX-01294-induced autophagy-related cell death through transcriptionally promoting the expression of p53 target genes. Taken together, our data suggest BIX-01294 induces autophagy-related cell death and selectively activates p53 target genes, which is repressed by SMYD2 methyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Autophagy-Related Proteins
  • Azepines / toxicity*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • HCT116 Cells
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Methylation / drug effects
  • Microtubule-Associated Proteins / metabolism
  • Quinazolines / toxicity*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sirolimus / toxicity
  • Transcriptome / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism

Substances

  • ATG9A protein, human
  • Autophagy-Related Proteins
  • Azepines
  • BIX 01294
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histones
  • MAP1LC3A protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Quinazolines
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Vesicular Transport Proteins
  • Histone-Lysine N-Methyltransferase
  • SMYD2 protein, human
  • ATG4A protein, human
  • Cysteine Endopeptidases
  • Sirolimus

Grants and funding

This work was supported by grants from the National Basic Research Program of China (973 Program, 2011CB504206 and 2012CB518700), the National Natural Science Foundation of China to Min Wu (30971502 and 91019013) and Lian-Yun Li (31221061, 31200653 and 31370866), and Program for New Century Excellent Talents in University to Min Wu (NCET-11-0410). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.