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Updated: Oct 18, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer
Shangwei Zhong1, Ji-Hak Jeong1,2, Changhao Huang1
1Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
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.
Insights
Indolethylamine N-methyltransferase (INMT) drives castration-resistant prostate cancer (CRPC) by detoxifying anticancer compounds. Targeting INMT or its regulator SMYD3 offers a promising therapeutic strategy for CRPC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Castration-resistant prostate cancer (CRPC) presents a significant clinical challenge with a poor prognosis.
- Current treatment options for CRPC are limited, necessitating the exploration of novel therapeutic targets.
Purpose of the Study:
- To investigate the role of indolethylamine N-methyltransferase (INMT) in the development and progression of CRPC.
- To identify epigenetic regulators of INMT and explore potential therapeutic strategies targeting INMT and its pathways.
Main Methods:
- RNA-seq, qPCR, Western blot, and immunohistochemistry were used to assess INMT expression in CRPC.
- ChIP assays identified SMYD3 as an epigenetic regulator of INMT. In vitro and in vivo models were used to evaluate therapeutic agents.
Main Results:
- INMT expression is significantly elevated in CRPC and correlates with poor patient prognosis.
- INMT promotes CRPC progression by detoxifying anticancer metabolites. Inhibition of INMT or its regulator SMYD3 suppressed CRPC development.
- Knockdown of INMT enhanced the efficacy of selenium compounds (MSA, MSC) and Bis(7)-tacrine against CRPC.
Conclusions:
- INMT is a key driver of castration resistance in prostate cancer through metabolic detoxification.
- Targeting INMT, its regulator SMYD3, or its methylation metabolites presents a viable therapeutic approach for CRPC.
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