Abstract
Abstract
Background
Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.
Methods
ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes’ expression and prognosis of ESCC.
Results
Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan–Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.
Conclusions
Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shaanxi Province
Publisher
Springer Science and Business Media LLC
Reference40 articles.
1. Ma Z, Liu D, Di S, Zhang Z, Li W, Zhang J, et al. Histone deacetylase 9 downregulation decreases tumor growth and promotes apoptosis in non-small cell lung cancer after melatonin treatment. J Pineal Res. 2019;67(2): e12587.
2. Ma Z, Xu L, Liu D, Zhang X, Di S, Li W, et al. Utilizing melatonin to alleviate side effects of chemotherapy: a potentially good partner for treating cancer with ageing. Oxid Med Cell Longev. 2020;2020:6841581.
3. Andrade C, Srihari BS, Reddy KP, Chandramma L. Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry. 2001;62(1):41–5.
4. Comperatore CA, Lieberman HR, Kirby AW, Adams B, Crowley JS. Melatonin efficacy in aviation missions requiring rapid deployment and night operations. Aviat Space Environ Med. 1996;67(6):520–4.
5. Pinato DJ, Stebbing J. Melatonin: resetting the clock of cancer progression? Lancet Oncol. 2016;17(1):23–4.
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