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Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer

BACKGROUND: Castration-resistant prostate cancer (CRPC) is associated with a very poor prognosis, and the treatment of which remains a serious clinical challenge. METHODS: RNA-seq, qPCR, western blot and immunohistochemistry were employed to identify and confirm the high expression of indolethylamin...

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Autores principales: Zhong, Shangwei, Jeong, Ji-Hak, Huang, Changhao, Chen, Xueyan, Dickinson, Shohreh Iravani, Dhillon, Jasreman, Yang, Li, Luo, Jun-Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482636/
https://www.ncbi.nlm.nih.gov/pubmed/34587977
http://dx.doi.org/10.1186/s13046-021-02109-z
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author Zhong, Shangwei
Jeong, Ji-Hak
Huang, Changhao
Chen, Xueyan
Dickinson, Shohreh Iravani
Dhillon, Jasreman
Yang, Li
Luo, Jun-Li
author_facet Zhong, Shangwei
Jeong, Ji-Hak
Huang, Changhao
Chen, Xueyan
Dickinson, Shohreh Iravani
Dhillon, Jasreman
Yang, Li
Luo, Jun-Li
author_sort Zhong, Shangwei
collection PubMed
description BACKGROUND: Castration-resistant prostate cancer (CRPC) is associated with a very poor prognosis, and the treatment of which remains a serious clinical challenge. METHODS: RNA-seq, qPCR, western blot and immunohistochemistry were employed to identify and confirm the high expression of indolethylamine N-methyltransferase (INMT) in CRPC and the clinical relevance. Chip assay was used to identify Histone-Lysine N-Methyltransferase (SMYD3) as a major epigenetic regulator of INMT. LC-MS/MS were used to identify new substrates of INMT methylation in CRPC tissues. Gene knockdown/overexpression, MTT and mouse cancer models were used to examine the role of INMT as well as the anticancer efficacy of INMT inhibitor N,N-dimethyltryptamine (DMT), the SMYD3 inhibitor BCl-12, the selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC), and the newly identified endogenous INMT substrate Bis(7)-tacrine. RESULTS: We found that the expression of INMT was highly increased in CRPC and was correlated with poor prognosis of clinical prostate cancer (PCa). INMT promoted PCa castration resistance via detoxification of anticancer metabolites. Knockdown of INMT or treatment with INMT inhibitor N,N-dimethyltryptamine (DMT) significantly suppressed CRPC development. Histone-Lysine N-Methyltransferase SMYD3 was a major epigenetic regulator of INMT expression, treatment with SMYD3 inhibitor BCl-121 suppressed INMT expression and inhibits CRPC development. Importantly, INMT knockdown significantly increased the anticancer effect of the exogenous selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC) as well as the endogenous metabolite Bis(7)-tacrine. CONCLUSIONS: Our study suggests that INMT drives PCa castration resistance through detoxification of anticancer metabolites, targeting INMT or its regulator SMYD3 or/and its methylation metabolites represents an effective therapeutic avenue for CRPC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02109-z.
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spelling pubmed-84826362021-10-04 Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer Zhong, Shangwei Jeong, Ji-Hak Huang, Changhao Chen, Xueyan Dickinson, Shohreh Iravani Dhillon, Jasreman Yang, Li Luo, Jun-Li J Exp Clin Cancer Res Research BACKGROUND: Castration-resistant prostate cancer (CRPC) is associated with a very poor prognosis, and the treatment of which remains a serious clinical challenge. METHODS: RNA-seq, qPCR, western blot and immunohistochemistry were employed to identify and confirm the high expression of indolethylamine N-methyltransferase (INMT) in CRPC and the clinical relevance. Chip assay was used to identify Histone-Lysine N-Methyltransferase (SMYD3) as a major epigenetic regulator of INMT. LC-MS/MS were used to identify new substrates of INMT methylation in CRPC tissues. Gene knockdown/overexpression, MTT and mouse cancer models were used to examine the role of INMT as well as the anticancer efficacy of INMT inhibitor N,N-dimethyltryptamine (DMT), the SMYD3 inhibitor BCl-12, the selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC), and the newly identified endogenous INMT substrate Bis(7)-tacrine. RESULTS: We found that the expression of INMT was highly increased in CRPC and was correlated with poor prognosis of clinical prostate cancer (PCa). INMT promoted PCa castration resistance via detoxification of anticancer metabolites. Knockdown of INMT or treatment with INMT inhibitor N,N-dimethyltryptamine (DMT) significantly suppressed CRPC development. Histone-Lysine N-Methyltransferase SMYD3 was a major epigenetic regulator of INMT expression, treatment with SMYD3 inhibitor BCl-121 suppressed INMT expression and inhibits CRPC development. Importantly, INMT knockdown significantly increased the anticancer effect of the exogenous selenium compounds methaneseleninic acid (MSA) and Se-(Methyl)selenocysteine hydrochloride (MSC) as well as the endogenous metabolite Bis(7)-tacrine. CONCLUSIONS: Our study suggests that INMT drives PCa castration resistance through detoxification of anticancer metabolites, targeting INMT or its regulator SMYD3 or/and its methylation metabolites represents an effective therapeutic avenue for CRPC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02109-z. BioMed Central 2021-09-29 /pmc/articles/PMC8482636/ /pubmed/34587977 http://dx.doi.org/10.1186/s13046-021-02109-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zhong, Shangwei
Jeong, Ji-Hak
Huang, Changhao
Chen, Xueyan
Dickinson, Shohreh Iravani
Dhillon, Jasreman
Yang, Li
Luo, Jun-Li
Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
title Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
title_full Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
title_fullStr Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
title_full_unstemmed Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
title_short Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
title_sort targeting inmt and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482636/
https://www.ncbi.nlm.nih.gov/pubmed/34587977
http://dx.doi.org/10.1186/s13046-021-02109-z
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