2. Academic Validation
  3. Phosphatase LHPP confers prostate cancer ferroptosis activation by modulating the AKT-SKP2-ACSL4 pathway

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

  • Cell Death Dis. 2024 Sep 11;15(9):665. doi: 10.1038/s41419-024-07007-8.
Guoqing Xie # 1 2,  Ningyang Li # 1 2,  Keqiang Li # 1 2,  Yating Xu 2 3,  Yu Zhang 1 2,  Shun Cao 1 2,  Budeng Huang 1 2,  Ruoyang Liu 1 2,  Peijie Zhou 1,  Yafei Ding 1,  Yinghui Ding 1,  Jinjian Yang 4,  Zhankui Jia 5,  Zhenlin Huang 6
Affiliations

Affiliations

  • 1 Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2 Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 3 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 4 Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. yangjinjian2011@126.com.
  • 5 Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. jiazhankui@126.com.
  • 6 Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. hzlinok@outlook.com.
  • # Contributed equally.
PMID: 39261475 DOI: 10.1038/s41419-024-07007-8
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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