Phosphatase LHPP confers prostate cancer ferroptosis activation by modulating the AKT-SKP2-ACSL4 pathway

• Published in: Cell death & disease 2024-09, Vol.15 (9), p.665-18, Article 665
• Main Authors: Xie, Guoqing, Li, Ningyang, Li, Keqiang, Xu, Yating, Zhang, Yu, Cao, Shun, Huang, Budeng, Liu, Ruoyang, Zhou, Peijie, Ding, Yafei, Ding, Yinghui, Yang, Jinjian, Jia, Zhankui, Huang, Zhenlin
• Format: Article
• Language: English
• Subjects: 13/106; 14/28; 38/32; 42/89; 631/154/309/507; 631/61/475; 631/67/589/466; 631/80/82; 692/53/2422; 82/51; 82/58; 82/80; 96/109; 96/95; AKT protein; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Cell proliferation; Coenzyme A Ligases - metabolism; Ferroptosis; Ferroptosis - drug effects; Histone Deacetylases - metabolism; Histones; Humans; Immunology; Inorganic Pyrophosphatase; Life Sciences; Lipid peroxidation; Lysosomes; Male; Medical prognosis; Mice; Mice, Nude; Phosphatase; Phosphorylation; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Skp2 protein; Tumor suppressor genes; Tumors; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• 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.