Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
Cell Death Dis. 2024 Sep 11;15(9):665. doi: 10.1038/s41419-024-07007-8.
LHPP, a novel, recognized tumor suppressor, exerts a critical influence on the regulation of tumor cell proliferation and survival by modulating various signaling pathways with its phosphatase activity. Here, we unveil a robust correlation between reduced LHPP expression and adverse prognosis in prostate cancer. We demonstrate that LHPP interacts with AKT, thereby dampening AKT phosphorylation and subsequently inhibiting ACSL4 phosphorylation at the T624 site. This interaction impedes phosphorylation-dependent ubiquitination, thwarting SKP2 from recognizing and binding to ACSL4 at the K621 site. As a result, ACSL4 is spared from lysosomal degradation, leading to its accumulation and the promotion of lipid peroxidation, and ferroptosis. Moreover, our findings reveal that Panobinostat, a potent histone-deacetylase inhibitor, intricately regulates LHPP expression at multiple levels through the inhibition of HDAC3. This complex modulation enhances the ferroptosis pathway, offering a novel mechanism for curtailing the growth of prostate tumors and highlighting its significant translational potential for clinical application.
LHPP 是一种新型的、公认的肿瘤抑制因子，通过其磷酸酶活性调节多种信号通路，对肿瘤细胞的增殖和存活产生关键影响。在这里，我们揭示了 LHPP 表达降低与前列腺癌不良预后之间存在显著相关性。我们证明 LHPP 与 AKT 相互作用，从而抑制 AKT 的磷酸化，并随后抑制 ACSL4 在 T624 位点的磷酸化。这种相互作用阻碍了磷酸化依赖性泛素化，阻止 SKP2 在 K621 位点识别并与 ACSL4 结合。结果，ACSL4 免于溶酶体降解，导致其积累并促进脂质过氧化和铁死亡。此外，我们的研究结果表明，一种强效的组蛋白去乙酰化酶抑制剂帕比司他（Panobinostat）通过抑制 HDAC3 在多个水平上复杂地调节 LHPP 的表达。这种复杂的调节增强了铁死亡途径，为抑制前列腺肿瘤的生长提供了一种新的机制，并突出了其在临床应用中的重要转化潜力。
