Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability

Zhi-Qiang Ma; Ying-Tong Feng; Kai Guo; Dong Liu; Chang-Jian Shao; Ming-Hong Pan; Yi-Meng Zhang; Yu-Xi Zhang; Di Lu; Di Huang; Fan Zhang; Jin-Liang Wang; Bo Yang; Jing Han; Xiao-Long Yan; Yi Hu

doi:10.1186/s40779-022-00412-0

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Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability

RESEARCH | Updated：2023-05-10

- Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability
- Military Medical Research Vol. 10, Issue 2, Pages: 207-226(2023)
- Affiliations：
  
  1.Department of Medical Oncology, Senior Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing 100853, China
  2.Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an 710038, China
  3.Department of Cardiothoracic Surgery, the 71th Group Army Hospital of PLA, the Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
  4.Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, the Third Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710068, China
  5.State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
  6.Department of Ophthalmology, Tangdu Hospital, the Fourth Military Medical University, Xi’an 710038, China
  7.Department of Cardiovascular Surgery, Xijing Hospital, the Fourth Military Medical University, Xi’an 710032, China
- Author bio：
  
  * hanjing@fmmu.edu.cn;
  yanxiaolong@fmmu.edu.cn;
  huyi301zlxb@sina.com
- Funds：
- DOI：10.1186/s40779-022-00412-0
  CLC：
- Published：2023-04
- Accepted：
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Cite this article as: Ma ZQ, Feng YT, Guo K, Liu D, Shao CJ, Pan MH, et al. Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability. Mil Med Res. 2022;9(1):54.
DOI：

Cite this article as: Ma ZQ, Feng YT, Guo K, Liu D, Shao CJ, Pan MH, et al. Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability. Mil Med Res. 2022;9(1):54. DOI： 10.1186/s40779-022-00412-0.

摘要

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 5-Ethynyl-2'-deoxyuridine (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 (

0.05). The expressions of HDAC7

c-Myc and USP10 in tumors were significantly higher than the paired normal tissues from 148 ESCC patients (

0.001). Then

the Kaplan-Meier survival analysis suggested that ESCC patients with high HDAC7

c-Myc or USP10 levels predicted worse overall survival (log-rank

0.001). Co-IP and Western blotting 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.

关键词

Keywords

references

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