School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
These authors contributed equally to this work.
Mol Cells. 2022 Apr 30;45(4):202-215. doi: 10.14348/molcells.2021.0206.
The androgen receptor (AR) is an important therapeutic target for treating prostate cancer (PCa). Moreover, there is an increasing need for understanding the AR-independent progression of tumor cells such as neuroendocrine prostate cancer (NEPC). Menin, which is encoded by multiple endocrine neoplasia type 1 (), serves as a direct link between AR and the mixed-lineage leukemia (MLL) complex in PCa development by activating AR target genes through histone H3 lysine 4 methylation. Although menin is a critical component of AR signaling, its tumorigenic role in AR-independent PCa cells remains unknown. Here, we compared the role of menin in AR-positive and AR-negative PCa cells via RNAi-mediated or pharmacological inhibition of menin. We demonstrated that menin was involved in tumor cell growth and metastasis in PCa cells with low or deficient levels of AR. The inhibition of menin significantly diminished the growth of PCa cells and induced apoptosis, regardless of the presence of AR. Additionally, transcriptome analysis showed that the expression of many metastasis-associated genes was perturbed by menin inhibition in AR-negative DU145 cells. Furthermore, wound-healing assay results showed that menin promoted cell migration in AR-independent cellular contexts. Overall, these findings suggest a critical function of menin in tumorigenesis and provide a rationale for drug development against menin toward targeting high-risk metastatic PCa, especially those independent of AR.
雄激素受体（AR）是治疗前列腺癌（PCa）的重要治疗靶点。此外，越来越需要了解肿瘤细胞（如神经内分泌前列腺癌（NEPC））的 AR 非依赖性进展。Menin 由多发性内分泌肿瘤 1 型（）编码，通过组蛋白 H3 赖氨酸 4 甲基化激活 AR 靶基因，在 PCa 发展中作为 AR 和混合谱系白血病（MLL）复合物之间的直接联系。尽管 Menin 是 AR 信号的关键组成部分，但它在 AR 非依赖性 PCa 细胞中的致癌作用尚不清楚。在这里，我们通过 RNAi 介导或 Menin 的药理学抑制比较了 Menin 在 AR 阳性和 AR 阴性 PCa 细胞中的作用。我们证明 Menin 参与了 AR 水平低或缺乏的 PCa 细胞中的肿瘤细胞生长和转移。抑制 Menin 显著减少了 PCa 细胞的生长并诱导了细胞凋亡，无论 AR 是否存在。此外，转录组分析表明，在 AR 阴性的 DU145 细胞中，许多与转移相关的基因的表达因 Menin 抑制而受到干扰。此外，划痕愈合测定结果表明，Menin 在 AR 非依赖性细胞环境中促进细胞迁移。总的来说，这些发现表明 Menin 在肿瘤发生中具有关键作用，并为针对高风险转移性 PCa 的 Menin 药物开发提供了依据，尤其是那些 AR 非依赖性的 PCa。
