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Melatonin disturbs SUMO ylation‐mediated crosstalk between c‐Myc and nestin via MT 1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells
Author(s) -
Lee Hyemin,
Lee HyoJung,
Jung Ji Hoon,
Shin Eun Ah,
Kim SungHoon
Publication year - 2018
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12496
Subject(s) - nestin , melatonin , chromatin immunoprecipitation , biology , microbiology and biotechnology , downregulation and upregulation , cancer research , immunoprecipitation , chemistry , stem cell , cell culture , gene expression , endocrinology , neural stem cell , biochemistry , promoter , gene , genetics
Here the underlying antitumor mechanism of melatonin and its potency as a sensitizer of paclitaxel was investigated in X02 cancer stem cells. Melatonin suppressed sphere formation and induced G2/M arrest in X02 cells expressing nestin, CD 133, CXCR 4, and SOX ‐2 as biomarkers of stemness. Furthermore, melatonin reduced the expression of CDK 2, CDK 4, cyclin D1, cyclin E, and c‐Myc and upregulated cyclin B1 in X02 cells. Notably, genes of c‐Myc related mRNA s were differentially expressed in melatonin‐treated X02 cells by microarray analysis. Consistently, melatonin reduced the expression of c‐Myc at mRNA and protein levels, which was blocked by MG 132. Of note, overexpression of c‐Myc increased the expression of nestin, while overexpression of nestin enhanced c‐Myc through crosstalk despite different locations, nucleus, and cytoplasm. Interestingly, melatonin attenuated small ubiquitin‐related modifier‐1 ( SUMO ‐1) more than SUMO ‐2 or SUMO ‐3 and disturbed nuclear translocation of nestin for direct binding to c‐Myc by SUMO ylation of SUMO ‐1 protein by immunofluorescence and immunoprecipitation. Also, melatonin reduced trimethylated histone H3K4me3 and H3K36me3 more than dimethylation in X02 cells by Western blotting and chromatin immunoprecipitation assay. Notably, melatonin upregulated MT 1, not MT 2, in X02 cells and melatonin receptor inhibitor luzindole blocked the ability of melatonin to decrease the expression of nestin, p‐c‐Myc(S62), and c‐Myc. Furthermore, melatonin promoted cytotoxicity, sub‐G1 accumulation, and apoptotic body formation by Paclitaxcel in X02 cells. Taken together, these findings suggest that melatonin inhibits stemness via suppression of c‐Myc, nestin, and histone methylation via MT 1 activation and promotes anticancer effect of Paclitaxcel in brain cancer stem cells.