Mechanism of lysine-specific demethylase 1 regulating castration resistance in prostate cancer via the matrix metalloproteinase-13/interleukin-17 signaling pathway

Li Haiying; Fan Xiujie; Fang Xiuxiu; Wang Yunshan

doi:10.13406/j.cnki.cyxb.003890

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Mechanism of lysine-specific demethylase 1 regulating castration resistance in prostate cancer via the matrix metalloproteinase-13/interleukin-17 signaling pathway

Precision medicine in cancer and translational studies | 更新时间：2025-12-31

- Mechanism of lysine-specific demethylase 1 regulating castration resistance in prostate cancer via the matrix metalloproteinase-13/interleukin-17 signaling pathway
- Journal of Chongqing Medical University Vol. 50, Issue 12, Pages: 1662-1672(2025)
- 作者机构：
  
  山东第一医科大学附属中心医院，济南 250013
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003890
  CLC： R737.25
- Received：24 November 2024，
  
  Revised：2024-12-25，
  
  Accepted：28 February 2025，
  
  Published：28 December 2025
- 稿件说明：
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李海英,范秀杰,方秀秀等.LSD1通过MMP13/IL-17途径调控前列腺癌去势抵抗性[J].重庆医科大学学报,2025,50(12):1662-1672.

Li Haiying,Fan Xiujie,Fang Xiuxiu,et al.Mechanism of lysine-specific demethylase 1 regulating castration resistance in prostate cancer via the matrix metalloproteinase-13/interleukin-17 signaling pathway[J].Journal of Chongqing Medical University,2025,50(12):1662-1672.
李海英,范秀杰,方秀秀等.LSD1通过MMP13/IL-17途径调控前列腺癌去势抵抗性[J].重庆医科大学学报,2025,50(12):1662-1672. DOI： 10.13406/j.cnki.cyxb.003890.

Li Haiying,Fan Xiujie,Fang Xiuxiu,et al.Mechanism of lysine-specific demethylase 1 regulating castration resistance in prostate cancer via the matrix metalloproteinase-13/interleukin-17 signaling pathway[J].Journal of Chongqing Medical University,2025,50(12):1662-1672. DOI： 10.13406/j.cnki.cyxb.003890.

摘要

目的

本研究旨在阐明赖氨酸特异性脱甲基酶 1（lysine specific demethylase 1，LSD1）在去势抵抗性前列腺癌（prostate cancer，PCa）中的作用及分子机制。

方法

通过利用癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据库进行生物信息学分析，探索LSD1在PCa中的差异表达和预后情况；为了构建雄激素非依赖性（androgen-independent，AI）细胞系，对PCa雄激素依赖细胞系前列腺癌淋巴结转移细胞系（lymph node carcinoma of the prostate cells，LNCap）进行雄激素剥夺处理，敲低LSD1观察细胞变化，并用LSD1抑制剂处理雄激素非依赖前列腺癌PC-3细胞系（Prostate Cancer-3 cell line，PC-3）；构建PCa原位瘤模型探究LSD1抑制对去势治疗敏感性的影响；最后通过转录组测序、实时荧光定量聚合酶链式反应（real-time fluorescence quantitative PCR，qPCR）和蛋白质印迹技术（Western blot，WB）和染色质免疫沉淀（chromatin immunoprecipitation，ChIP）实验探索机制。

结果

LSD1在TCGA-PCa及去势抵抗性PCa中明显上调，高表达患者生存期短，且在LNCap-AI细胞中表达高于LNCap细胞，敲低LSD1可抑制细胞恶性行为、提高凋亡水平，LSD1抑制剂能抑制PC-3细胞恶性行为，抑制LSD1可提高PCa对去势治疗的敏感性，LSD1敲低降低基质金属蛋白酶13（Matrix Metalloproteinase 13，MMP13）的表达、抑制白细胞介素-17（interleukin-17，IL-17）信号通路，并通过调节MMP13基因启动子区域组蛋白H3第9位赖氨酸（histone H3 lysine 9，H3K9）的甲基化水平调控其表达。

结论

LSD1通过调节MMP13基因启动子区域H3K9的甲基化水平控制MMP13表达，进而影响IL-17信号通路，在前列腺癌去势抵抗性进程中发挥重要作用。

Abstract

Objective

This study aimed to elucidate the role and molecular mechanism of lysine specific demethylase 1（LSD1） in castration-resistant prostate cancer（PCa）.

Methods

Bioinformatics analysis was conducted using The Cancer Genome Atlas（TCGA） database to explore the differential expression and prognostic significance of LSD1 in PCa. An androgen-independent（AI） cell line was established by subjecting the androgen-dependent LNCap cell line of PCa to androgen deprivation. The effects of LSD1 knockdown on cell characteristics were observed，and the androgen-independent PC-3 cells were treated with the LSD1 inhibitor. A PCa orthotopic tumor model was constructed to investigate the impact of LSD1 inhibition on the sensitivity of PCa to castration therapy. Finally，transcriptome sequencing，real-time fluorescence quantitative PCR（qPCR），Western blot，and chromatin immunoprecipitation （ChIP） assays were performed to explore the underlying mechanisms.

Results

LSD1 was significantly upregulated in TCGA-PCa and castration-resistant PCa. Patients with high LSD1 expression had shorter survival times. The expression of LSD1 was higher in LNCap-AI cells compared to LNCap cells. LSD1 knockdown inhibited the malignant behavior of cells and increased apoptosis. The LSD1 inhibitor suppressed the malignant behavior of PC-3 cells. Inhibition of LSD1 enhanced the sensitivity of PCa to castration therapy. Mechanistically，LSD1 knockdown decreased the expression of Matrix Metalloproteinase 13（MMP13） and inhibited the interleukin-17（IL-17） signaling pathway. LSD1 regulated the expression of MMP13 by modulating the methylation level of the H3K9 region in the MMP13 gene promoter.

Conclusion

LSD1 controls the expression of MMP13 by regulating the methylation level of the H3K9 region in the MMP13 gene promoter，thereby influencing the IL17 signaling pathway and playing a crucial role in the progression of castration resistance in prostate cancer.

关键词

Keywords

references

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