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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1007006/full |
| _version_ | 1811258811033321472 |
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| author | Lu Bai Siwen Sun Wenmei Su Chaoqun Chen Yuesheng Lv Jinrui Zhang Jinyao Zhao Man Li Yangfan Qi Wenjing Zhang Yang Wang Yang Wang |
| author_facet | Lu Bai Siwen Sun Wenmei Su Chaoqun Chen Yuesheng Lv Jinrui Zhang Jinyao Zhao Man Li Yangfan Qi Wenjing Zhang Yang Wang Yang Wang |
| author_sort | Lu Bai |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T18:21:05Z |
| format | Article |
| id | doaj.art-d51317a0daff4486bfab5508b3a261d9 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T18:21:05Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d51317a0daff4486bfab5508b3a261d92022-12-22T03:21:27ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.10070061007006Melatonin inhibits HCC progression through regulating the alternative splicing of NEMOLu Bai0Siwen Sun1Wenmei Su2Chaoqun Chen3Yuesheng Lv4Jinrui Zhang5Jinyao Zhao6Man Li7Yangfan Qi8Wenjing Zhang9Yang Wang10Yang Wang11Institute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaDepartment of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, ChinaInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaDepartment of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaDepartment of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaInstitute of Cancer Stem Cell, Dalian Medical University, Dalian, ChinaDepartment of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, ChinaHepatocellular 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.https://www.frontiersin.org/articles/10.3389/fphar.2022.1007006/fullmelatoninHCCNEMOalternative splicingMT1 |
| spellingShingle | Lu Bai Siwen Sun Wenmei Su Chaoqun Chen Yuesheng Lv Jinrui Zhang Jinyao Zhao Man Li Yangfan Qi Wenjing Zhang Yang Wang Yang Wang Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO Frontiers in Pharmacology melatonin HCC NEMO alternative splicing MT1 |
| 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 | melatonin HCC NEMO alternative splicing MT1 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1007006/full |
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