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Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma

OBJECTIVE: To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. METHODS: CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocula...

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Autores principales: Zhuang, Ai, Chai, Peiwei, Wang, Shaoyun, Zuo, Sipeng, Yu, Jie, Jia, Shichong, Ge, Shengfang, Jia, Renbing, Zhou, Yixiong, Shi, Wodong, Xu, Xiaofang, Ruan, Jing, Fan, Xianqun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787022/
https://www.ncbi.nlm.nih.gov/pubmed/35075807
http://dx.doi.org/10.1002/ctm2.660
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author Zhuang, Ai
Chai, Peiwei
Wang, Shaoyun
Zuo, Sipeng
Yu, Jie
Jia, Shichong
Ge, Shengfang
Jia, Renbing
Zhou, Yixiong
Shi, Wodong
Xu, Xiaofang
Ruan, Jing
Fan, Xianqun
author_facet Zhuang, Ai
Chai, Peiwei
Wang, Shaoyun
Zuo, Sipeng
Yu, Jie
Jia, Shichong
Ge, Shengfang
Jia, Renbing
Zhou, Yixiong
Shi, Wodong
Xu, Xiaofang
Ruan, Jing
Fan, Xianqun
author_sort Zhuang, Ai
collection PubMed
description OBJECTIVE: To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. METHODS: CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. RESULTS: Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. CONCLUSIONS: Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation.
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spelling pubmed-87870222022-01-31 Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma Zhuang, Ai Chai, Peiwei Wang, Shaoyun Zuo, Sipeng Yu, Jie Jia, Shichong Ge, Shengfang Jia, Renbing Zhou, Yixiong Shi, Wodong Xu, Xiaofang Ruan, Jing Fan, Xianqun Clin Transl Med Research Articles OBJECTIVE: To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. METHODS: CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. RESULTS: Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. CONCLUSIONS: Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation. John Wiley and Sons Inc. 2022-01-24 /pmc/articles/PMC8787022/ /pubmed/35075807 http://dx.doi.org/10.1002/ctm2.660 Text en © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhuang, Ai
Chai, Peiwei
Wang, Shaoyun
Zuo, Sipeng
Yu, Jie
Jia, Shichong
Ge, Shengfang
Jia, Renbing
Zhou, Yixiong
Shi, Wodong
Xu, Xiaofang
Ruan, Jing
Fan, Xianqun
Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
title Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
title_full Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
title_fullStr Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
title_full_unstemmed Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
title_short Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
title_sort metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787022/
https://www.ncbi.nlm.nih.gov/pubmed/35075807
http://dx.doi.org/10.1002/ctm2.660
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