title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Jia-Dong
authors.initials: JD
authors.lastname: Fan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Pin-Ji
authors.initials: PJ
authors.lastname: Lei
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Development Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Shangze
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Yi-Lei
authors.initials: YL
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Zhao-Ning
authors.initials: ZN
authors.lastname: Wang
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Cell Biology and Development Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Lian-Yun
authors.initials: LY
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071183:Autophagy-Related Proteins; D001381:Azepines / Q000633:toxicity*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011799:Quinazolines / Q000633:toxicity*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020123:Sirolimus / Q000633:toxicity; D059467:Transcriptome / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D001381:Azepines; C518299:BIX 01294; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D033921:Vesicular Transport Proteins; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human; C474025:ATG4A protein, human; D003546:Cysteine Endopeptidases; D020123:Sirolimus