Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
| Autor: | Jun-Li Luo, Ji-Hak Jeong, Xueyan Chen, Shangwei Zhong, Li Yang, Changhao Huang, Shohreh I. Dickinson, Jasreman Dhillon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Prostate cancer castration-resistance Apoptosis urologic and male genital diseases Gene Expression Regulation Enzymologic Epigenesis Genetic MSC Mice Prostate cancer chemistry.chemical_compound Bis(7)-tacrine MSA Tumor Cells Cultured medicine Animals Humans Epigenetics Enzyme Inhibitors RC254-282 Cell Proliferation Gene knockdown INMT SMYD3 Research DMT Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Histone-Lysine N-Methyltransferase Methyltransferases Methylation DNA Methylation Prognosis medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Prostatic Neoplasms Castration-Resistant Methaneseleninic acid Oncology chemistry Tacrine Cancer research medicine.drug |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-14 (2021) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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