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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.
Afiliación
  • Zhong S; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • Jeong JH; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • Huang C; College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • Chen X; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • Dickinson SI; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
  • Dhillon J; Department of Pathology, Moffitt Cancer Center, 2902 Magnolia Drive, Tampa, FL, 33612, USA.
  • Yang L; Department of Pathology, Moffitt Cancer Center, 2902 Magnolia Drive, Tampa, FL, 33612, USA.
  • Luo JL; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA. yangli0727@zzu.edu.cn.
J Exp Clin Cancer Res ; 40(1): 307, 2021 Sep 29.
Article en En | MEDLINE | ID: mdl-34587977
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Enzimológica de la Expresión Génica / Regulación Neoplásica de la Expresión Génica / N-Metiltransferasa de Histona-Lisina / Metilación de ADN / Inhibidores Enzimáticos / Neoplasias de la Próstata Resistentes a la Castración / Metiltransferasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Exp Clin Cancer Res Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Enzimológica de la Expresión Génica / Regulación Neoplásica de la Expresión Génica / N-Metiltransferasa de Histona-Lisina / Metilación de ADN / Inhibidores Enzimáticos / Neoplasias de la Próstata Resistentes a la Castración / Metiltransferasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Exp Clin Cancer Res Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido