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Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO

Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tu...

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Autores principales: Bai, Lu, Sun, Siwen, Su, Wenmei, Chen, Chaoqun, Lv, Yuesheng, Zhang, Jinrui, Zhao, Jinyao, Li, Man, Qi, Yangfan, Zhang, Wenjing, Wang, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9548564/
https://www.ncbi.nlm.nih.gov/pubmed/36225557
http://dx.doi.org/10.3389/fphar.2022.1007006
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author Bai, Lu
Sun, Siwen
Su, Wenmei
Chen, Chaoqun
Lv, Yuesheng
Zhang, Jinrui
Zhao, Jinyao
Li, Man
Qi, Yangfan
Zhang, Wenjing
Wang, Yang
author_facet Bai, Lu
Sun, Siwen
Su, Wenmei
Chen, Chaoqun
Lv, Yuesheng
Zhang, Jinrui
Zhao, Jinyao
Li, Man
Qi, Yangfan
Zhang, Wenjing
Wang, Yang
author_sort Bai, Lu
collection PubMed
description Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tumor growth through regulating RNA alternative splicing remains largely unknown. Here we demonstrated that melatonin could inhibit the growth of HCC. Mechanistically, melatonin induced transcriptional alterations of genes, which are involved in DNA replication, DNA metabolic process, DNA repair, response to wounding, steroid metabolic process, and extracellular matrix functions. Importantly, melatonin controlled numerous cancer-related RNA alternative splicing events, regulating mitotic cell cycle, microtubule-based process, kinase activity, DNA metabolic process, GTPase regulator activity functions. The regulatory effect of melatonin on alternative splicing is partially mediated by melatonin receptor MT1. Specifically, melatonin regulates the splicing of IKBKG (NEMO), an essential modulator of NF-κB. In brief, melatonin increased the production of the long isoform of NEMO-L with exon 5 inclusion, thereby inhibiting the growth of HepG2 cells. Collectively, our study provides a novel mechanism of melatonin in regulating RNA alternative splicing, and offers a new perspective for melatonin in the inhibition of cancer progression.
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spelling pubmed-95485642022-10-11 Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO Bai, Lu Sun, Siwen Su, Wenmei Chen, Chaoqun Lv, Yuesheng Zhang, Jinrui Zhao, Jinyao Li, Man Qi, Yangfan Zhang, Wenjing Wang, Yang Front Pharmacol Pharmacology Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tumor growth through regulating RNA alternative splicing remains largely unknown. Here we demonstrated that melatonin could inhibit the growth of HCC. Mechanistically, melatonin induced transcriptional alterations of genes, which are involved in DNA replication, DNA metabolic process, DNA repair, response to wounding, steroid metabolic process, and extracellular matrix functions. Importantly, melatonin controlled numerous cancer-related RNA alternative splicing events, regulating mitotic cell cycle, microtubule-based process, kinase activity, DNA metabolic process, GTPase regulator activity functions. The regulatory effect of melatonin on alternative splicing is partially mediated by melatonin receptor MT1. Specifically, melatonin regulates the splicing of IKBKG (NEMO), an essential modulator of NF-κB. In brief, melatonin increased the production of the long isoform of NEMO-L with exon 5 inclusion, thereby inhibiting the growth of HepG2 cells. Collectively, our study provides a novel mechanism of melatonin in regulating RNA alternative splicing, and offers a new perspective for melatonin in the inhibition of cancer progression. Frontiers Media S.A. 2022-09-26 /pmc/articles/PMC9548564/ /pubmed/36225557 http://dx.doi.org/10.3389/fphar.2022.1007006 Text en Copyright © 2022 Bai, Sun, Su, Chen, Lv, Zhang, Zhao, Li, Qi, Zhang and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Bai, Lu
Sun, Siwen
Su, Wenmei
Chen, Chaoqun
Lv, Yuesheng
Zhang, Jinrui
Zhao, Jinyao
Li, Man
Qi, Yangfan
Zhang, Wenjing
Wang, Yang
Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO
title Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO
title_full Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO
title_fullStr Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO
title_full_unstemmed Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO
title_short Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO
title_sort melatonin inhibits hcc progression through regulating the alternative splicing of nemo
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9548564/
https://www.ncbi.nlm.nih.gov/pubmed/36225557
http://dx.doi.org/10.3389/fphar.2022.1007006
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