针对 INMT 并阻断其甲基化途径治疗去势抵抗性前列腺癌。
Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer.
机构信息
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
出版信息
J Exp Clin Cancer Res. 2021 Sep 29;40(1):307. doi: 10.1186/s13046-021-02109-z.
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.
背景
去势抵抗性前列腺癌（CRPC）与预后极差相关，其治疗仍然是一个严峻的临床挑战。
方法
采用 RNA-seq、qPCR、western blot 和免疫组化技术来鉴定和确认吲哚乙胺 N-甲基转移酶（INMT）在 CRPC 中的高表达及其临床相关性。芯片检测用于鉴定组蛋白赖氨酸 N-甲基转移酶（SMYD3）作为 INMT 的主要表观遗传调控因子。LC-MS/MS 用于鉴定 CRPC 组织中 INMT 甲基化的新底物。基因敲低/过表达、MTT 和小鼠癌症模型用于研究 INMT 的作用以及 INMT 抑制剂 N，N-二甲基色胺（DMT）、SMYD3 抑制剂 BCl-12、硒化合物甲硒酸（MSA）和（甲基）硒代半胱氨酸盐酸盐（MSC）以及新鉴定的内源性 INMT 底物双（7）-他克林的抗癌功效。
结果
我们发现 INMT 在 CRPC 中高度表达，并与临床前列腺癌（PCa）的不良预后相关。INMT 通过解毒抗癌代谢物促进 PCa 去势抵抗。敲低 INMT 或用 INMT 抑制剂 N，N-二甲基色胺（DMT）治疗可显著抑制 CRPC 的发展。组蛋白赖氨酸 N-甲基转移酶 SMYD3 是 INMT 表达的主要表观遗传调控因子，用 SMYD3 抑制剂 BCl-12 处理可抑制 INMT 表达并抑制 CRPC 的发展。重要的是，INMT 敲低显著增加了外源性硒化合物甲硒酸（MSA）和（甲基）硒代半胱氨酸盐酸盐（MSC）以及内源性代谢物双（7）-他克林的抗癌效果。
结论
我们的研究表明，INMT 通过解毒抗癌代谢物驱动 PCa 去势抵抗，靶向 INMT 或其调节剂 SMYD3 或/和其甲基化代谢物是治疗 CRPC 的有效治疗途径。
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