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

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 Sep 27;9(1):54. doi: 10.1186/s40779-022-00412-0.
Zhi-Qiang Ma  # 1 2,  Ying-Tong Feng  # 2 3,  Kai Guo  # 2 4,  Dong Liu  # 5,  Chang-Jian Shao 2,  Ming-Hong Pan 2,  Yi-Meng Zhang 6,  Yu-Xi Zhang 7,  Di Lu 1,  Di Huang 1,  Fan Zhang 1,  Jin-Liang Wang 1,  Bo Yang 1,  Jing Han 8,  Xiao-Long Yan 9,  Yi Hu 10
Affiliations

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.
  • 8 Department of Ophthalmology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, 710038, China. hanjing@fmmu.edu.cn.
  • 9 Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, 710038, China. yanxiaolong@fmmu.edu.cn.
  • 10 Department of Medical Oncology, Senior Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China. huyi301zlxb@sina.com.
  • # Contributed equally.
PMID: 36163081 DOI: 10.1186/s40779-022-00412-0
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.

Keywords

Esophageal squamous cell carcinoma (ESCC); Histone deacetylase 7 (HDAC7); Melatonin; Ubiquitin-specific peptidase 10 (USP10); c-Myc; β-catenin.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z