Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

Abstract

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, CD133, CXCR4, and SOX-2 as biomarkers of stemness. Furthermore, melatonin reduced the expression of CDK2, CDK4, cyclin D1, cyclin E, and c-Myc and upregulated cyclin B1 in X02 cells. Notably, genes of c-Myc related mRNAs 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 MG132. 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 SUMOylation 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 MT1, not MT2, 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 MT1 activation and promotes anticancer effect of Paclitaxcel in brain cancer stem cells.

Targeting miR‐193a‐AML1‐ETO‐β‐catenin axis by melatonin suppresses the self‐renewal of leukaemia stem cells in leukaemia with t (8;21) translocation

“…Our results indicate that MLT decreases the expression of β‐catenin and overexpression of β‐catenin partially prevents MLT‐induced anti‐self‐renewal, suggesting that MLT presents anti‐self‐renewal activity through AML1‐ETO‐β‐catenin axis. Consistent with our results, MLT has been reported to promote the anticancer effect of paclitaxcel in brain cancer stem cells . Most importantly, MLT has little effect on the colony formation in normal human and murine HSPC.…”

The emergence of melatonin in oncology: Focus on colorectal cancer

“…Melatonin is relevant in targeting CSC because they exhibit circadian rhythmicity. In accordance with the foregoing, melatonin clearly has demonstrated debilitating effects on tumor cells, but also specific oncostatic actions on subpopulations of colorectal and noncolorectal CSC. Thus, melatonin administration (10 mg/day, IP for 2 weeks) to male rats exposed to constant light and treated with the CRC carcinogen DMH, reduced the incidence of aberrant crypt foci, diminished the development of preneoplastic and dysplastic lesions in pericryptal colonic stroma, and stimulated apoptosis and, thereby, prevented CRC, probably through the control of reproduction and differentiation of CSC.…”

The effects of melatonin on signaling pathways and molecules involved in glioma

“…New evidence suggests that nestin and c‐myc play an important role in stem cell signaling pathways . In general, myc proteins affect the physiological conditions in biological processes, including growth, differentiation, and apoptosis .…”

“…Although these two markers are located in different places of the cell, the excessive c‐myc expression increases nestin expression, which in turn increases c‐myc expression through cross talk. Melatonin suppresses the stemness by inhibiting cross talk between nestin and c‐myc .…”

“…In addition, melatonin has antioxidant, anti‐tumor, and anti‐inflammatory effects in diverse cancers . Effect of this hormone is inhibiting the proliferation of glioma cells in vitro and in vivo .…”