Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Oncogene. 2023 Jun;42(26):2126-2138. doi: 10.1038/s41388-023-02718-2. Epub 2023 May 17.
The hormonal transcription factor androgen receptor (AR) is a master regulator of prostate cancer (PCa). Protein palmitoylation, which attaches a palmitate fatty acid to a substrate protein, is mediated by a class of 23 ZDHHC (Zinc-Finger DHHC motif)-family palmitoyltransferases. Although palmitoylation has been shown to modify many proteins and regulate diverse cellular processes, little is known about ZDHHC genes in cancer. Here we examined ZDHHC family gene expression in human tissue panels and identified ZDHHC7 as a PCa-relevant member. RNA-seq analyses of PCa cells with ZDHHC7 de-regulation revealed global alterations in androgen response and cell cycle pathways. Mechanistically, ZDHHC7 inhibits AR gene transcription and therefore reduces AR protein levels and abolishes AR signaling in PCa cells. Accordingly, ZDHHC7 depletion increased the oncogenic properties of PCa cells, whereas restoring ZDHHC7 is sufficient to suppress PCa cell proliferation and invasion in vitro and mitigate xenograft tumor growth in vivo. Lastly, we demonstrated that ZDHHC7 is downregulated in human PCa compared to benign-adjacent tissues, and its loss is associated with worse clinical outcomes. In summary, our study reveals a global role of ZDHHC7 in inhibiting androgen response and suppressing PCa progression and identifies ZDHHC7 loss as a biomarker for aggressive PCa and a target for therapeutic intervention.
激素转录因子雄激素受体 (AR) 是前列腺癌 (PCa) 的主要调节因子。蛋白质棕榈酰化是通过一类 23 个 ZDHHC（锌指 DHHC 基序）家族棕榈酰转移酶将棕榈酸脂肪酸连接到底物蛋白上介导的。尽管已经表明棕榈酰化可以修饰许多蛋白质并调节多种细胞过程，但关于癌症中的 ZDHHC 基因知之甚少。在这里，我们检查了人类组织面板中的 ZDHHC 家族基因表达，并确定 ZDHHC7 是与 PCa 相关的成员。ZDHHC7 失调的 PCa 细胞的 RNA-seq 分析显示雄激素反应和细胞周期途径的全局改变。在机制上，ZDHHC7 抑制 AR 基因转录，从而降低 PCa 细胞中的 AR 蛋白水平并消除 AR 信号。因此，ZDHHC7 的耗竭增加了 PCa 细胞的致癌特性，而恢复 ZDHHC7 足以抑制体外 PCa 细胞的增殖和侵袭，并减轻体内异种移植物肿瘤的生长。最后，我们证明与良性相邻组织相比，ZDHHC7 在人 PCa 中下调，并且其缺失与更差的临床结果相关。总之，我们的研究揭示了 ZDHHC7 在抑制雄激素反应和抑制 PCa 进展中的全局作用，并确定 ZDHHC7 缺失是侵袭性 PCa 的生物标志物和治疗干预的靶点。
