The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, P R China.
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
Cell Death Dis. 2024 Nov 6;15(11):796. doi: 10.1038/s41419-024-07142-2.
Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.
神经内分泌前列腺癌（NEPC）是前列腺腺癌在内分泌治疗失败后发生的，提示其致死率高且治疗选择有限。解析从腺癌向 NEPC 转化的分子机制可能提供有价值的治疗策略。我们进行了泛癌症差异 mRNA 丰度分析，发现驱动蛋白家族成员 1A（KIF1A）在 NEPC 中高表达。KIF1A 敲低会损害神经内分泌（NE）特征，包括 NE 标记基因表达、干性和上皮-间充质转化（EMT），而过表达 KIF1A 则促进这些过程。靶向 KIF1A 抑制了体外和体内 NE 分化的前列腺癌细胞的生长。在机制上，KIF1A 与 O-连接的 N-乙酰葡萄糖胺转移酶（OGT）结合并调节其蛋白表达和活性。KIF1A 过表达引起的 OGT 核内积累促进了核内β-连环蛋白和 OCT4 的核内 O-GlcNAcylation。更重要的是，我们的数据表明 OGT 对于 KIF1A 诱导的 NE 分化和侵袭性肿瘤生长至关重要。一种 OGT 抑制剂，OSMI-1，可显著抑制体外 NE 分化的前列腺癌细胞增殖和体内肿瘤生长。我们的研究结果表明，KIF1A 通过调节 OGT 介导的 O-GlcNAcylation 促进 NE 向 NEPC 的分化。靶向 O-GlcNAcylation 可能会阻碍一组 KIF1A 表达升高的前列腺癌患者中 NEPC 的发展。
