Hong Sung Pyo, Kim Kil Won, Ahn Soon Kil
Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 22012, Republic of Korea.
Curr Issues Mol Biol. 2023 Jun 27;45(7):5347-5361. doi: 10.3390/cimb45070339.
The Hedgehog (Hh) signaling pathway plays an essential role in the initiation and progression of prostate cancer. This is mediated by transcriptional factors belonging to the GLI (glioma-associated oncogene) family, which regulate downstream targets to drive prostate cancer progression. The activity of GLI proteins is tightly controlled by a range of mechanisms, including molecular interactions and post-translational modifications. In particular, mitogenic and oncogenic signaling pathways have been shown to regulate GLI protein activity independently of upstream Hh pathway signaling. Identifying GLI protein regulators is critical for the development of targeted therapies that can improve patient outcomes. This study aimed to identify a novel protein that directly regulates the activity of GLI transcription factors in prostate cancer. We performed gene expression, cellular analyses, and reporter assays to demonstrate that DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) interacts with GLI1 and GLI2, the master regulators of Hh signaling. Interestingly, DAX1 overexpression significantly inhibited Hh signaling by reducing GLI1 and GLI2 activity, prostate cancer cell proliferation, and viability. Our results shed light on a novel regulatory mechanism of Hh signaling in prostate cancer cells. The interaction between DAX1 and GLI transcription factors provides insight into the complex regulation of Hh signaling in prostate cancer. Given the importance of Hh signaling in prostate cancer progression, targeting DAX1-GLI interactions may represent a promising therapeutic approach against prostate cancer. Overall, this study provides new insights into the regulation of the Hh pathway and its role in prostate cancer progression. The findings suggest that DAX1 could serve as a potential therapeutic target for the treatment of prostate cancer.
刺猬信号通路（Hh）在前列腺癌的发生和发展中起着至关重要的作用。这是由属于GLI（胶质瘤相关致癌基因）家族的转录因子介导的，这些转录因子调节下游靶点以驱动前列腺癌的进展。GLI蛋白的活性受到一系列机制的严格控制，包括分子相互作用和翻译后修饰。特别是，有丝分裂和致癌信号通路已被证明可独立于上游Hh信号通路调节GLI蛋白活性。识别GLI蛋白调节剂对于开发能够改善患者预后的靶向治疗至关重要。本研究旨在鉴定一种直接调节前列腺癌中GLI转录因子活性的新型蛋白质。我们进行了基因表达、细胞分析和报告基因检测，以证明DAX1（X染色体上剂量敏感型性反转肾上腺发育不全先天性关键区域基因1）与Hh信号的主要调节因子GLI1和GLI2相互作用。有趣的是，DAX1过表达通过降低GLI1和GLI2活性、前列腺癌细胞增殖和活力，显著抑制了Hh信号。我们的结果揭示了前列腺癌细胞中Hh信号的一种新型调节机制。DAX1与GLI转录因子之间的相互作用为深入了解前列腺癌中Hh信号的复杂调节提供了线索。鉴于Hh信号在前列腺癌进展中的重要性，靶向DAX1-GLI相互作用可能是一种有前景的前列腺癌治疗方法。总体而言，本研究为Hh信号通路的调节及其在前列腺癌进展中的作用提供了新的见解。研究结果表明，DAX1可能作为治疗前列腺癌的潜在治疗靶点。
