蛋白激酶B
磷酸化
癌症研究
SKP2型
前列腺癌
信号转导
PI3K/AKT/mTOR通路
磷酸酶
化学
细胞生物学
生物
癌症
泛素
泛素连接酶
生物化学
遗传学
基因
作者
Guoqing Xie,Ningyang Li,Keqiang Li,Yating Xu,Yukui Zhang,Shuai Cao,Budeng Huang,Ruoyang Liu,Peijie Zhou,Yafei Ding,Yinghui Ding,Jinjian Yang,Zhankui Jia,Zhenlin Huang
标识
DOI:10.1038/s41419-024-07007-8
摘要
Abstract 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.
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