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


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.

SUBMITTER: Fan JD 

PROVIDER: S-EPMC4285553 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Fan Jia-Dong JD   Lei Pin-Ji PJ   Zheng Jun-Yi JY   Wang Xiang X   Li Shangze S   Liu Huan H   He Yi-Lei YL   Wang Zhao-Ning ZN   Wei Gang G   Zhang Xiaodong X   Li Lian-Yun LY   Wu Min M  

PloS one 20150106 1


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 methylati  ...[more]

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