Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis

Abstract

Glioblastoma stem-like cells (GSCs) play essential roles in glioma growth, radio- and chemo-resistance, and recurrence. Elimination of GSCs has therefore become a key strategy and challenge in glioblastoma therapy. Here, we show that melatonin, an indolamine derived from I-tryptophan, significantly inhibited viability and self-renewal ability of GSCs accompanied by a decrease of stem cell markers. We have identified EZH2-NOTCH1 signaling as the key signal pathway that regulated the effects of melatonin in the GSCs. Instead of transcriptionally silencing gene expression by generating a methylated epigenetic mark at histone 3 at lysine 27 (H3K27), EZH2 regulates NOTCH1 expression by directly binding to the NOTCH1 promoter. Moreover, correlation between the expressions of EZH2 and NOTCH intracellular domain 1 (NICD1) was observed in the clinical tumor samples, evidently supporting the existence of EZH2-NOTCH1 interaction in the gliomas and GSCs. Collectively, we demonstrated that melatonin, a potential tumor inhibitor, performs its function partly by suppressing GSC properties through EZH2-NOTCH1 signaling axis.

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

“…Melatonin (N‐acetyl‐5‐methoxytryptamine), a circardian and circannual cycle regulator, was also known to have antioxidant, anti‐inflammatory, and antitumor effects in various cancers such as brain, lung, breast, prostate, leukemia, colon, and liver cancers. Recently, melatonin was reported to suppress the growth of glioblastoma stem cells via inhibition of EZH2‐Notch1 or Akt‐EZH2‐Stat3 signaling pathways.…”

Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals

“…Melatonin has been shown to inhibit proliferation of many types of cancer cells such as glioblastoma cells, colon cancer cells, and breast cancer cells (49)(50)(51). Melatonin exerts its anti-proliferative activity by inactivating FoxO-1 and NF-κB transcription factors, downregulating myosin light chain kinase expression through cross-talk with p38 MAPK, or by suppressing Notch1 signaling (49,52,53). It remains to be tested whether melatonin is involved in goblet cell differentiation by regulating Notch1 expression.…”

“…Melatonin, which is synthesized from tryptophan by enzymes N-acetyltransferase and acetylserotonin methyltransferase, is produced in many tissues, including the gastrointestinal tract as well as in the pineal gland (47,48). Melatonin has been shown to inhibit proliferation of many types of cancer cells such as glioblastoma cells, colon cancer cells, and breast cancer cells (49)(50)(51). Melatonin exerts its anti-proliferative activity by inactivating FoxO-1 and NF-κB transcription factors, downregulating myosin light chain kinase expression through cross-talk with p38 MAPK, or by suppressing Notch1 signaling (49,52,53).…”

Melatonin’s Antineoplastic Potential Against Glioblastoma

“…The downregulation of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) may in part explain the inhibitory effect of melatonin on GSCs. Zheng et al [85], studying the knockdown of EZH2 in GBM cells, observed a significant downregulation of Notch1, a transmembrane protein with an important role in cell embryonic and postnatal development [85][86][87][88] that is overexpressed in many cancer types, like breast, lung, pancreatic, and colon cancer [88]. The depletion of EZH2 also reduced the quantity and self-renewal activity of GSCs.…”