J Cancer Prev.
2024 Dec;29(4):129-139. 10.15430/JCP.24.031.
Non-canonical Function of Prolyl Hydroxylase Domain 2 in Breast Cancer Cell Growth and Progression: Role of Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1
- Affiliations
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- 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
- 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
- 3Department of Pharmacy, Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
- 4MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
- 5Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul, Korea
- 6Cancer Research Institute, Seoul National University, Seoul, Korea
- KMID: 2564114
- DOI: http://doi.org/10.15430/JCP.24.031
Abstract
- Prolyl hydroxylase domain 2 (PHD2) is the primary oxygen sensing enzyme involved in hydroxylation of hypoxia-inducible factor (HIF). Under normoxic conditions, PHD2 hydroxylates specific proline residues in HIF-1α and HIF-2α, promoting their ubiquitination and subsequent proteasomal degradation. Although PHD2 activity decreases in hypoxia, notable residual activity persists, but its function in these conditions remains unclear. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) targets proteins with phosphorylated serine/threonine-proline (pSer/Thr-Pro) motifs. As PHD2 contains several pSer/Thr-Pro motifs, it may be a potential substrate of Pin1. In the present study, we found Pin1 and PHD2 interactions in human breast cancer MDA-MB-231 cells. The breast cancer tissue array revealed higher levels of PHD2 and Pin1 in tumors compared to adjacent normal tissues. Through liquid chromatography-tandem mass spectrometry spectrometry, three phosphorylation sites (S125, T168, and S174) on PHD2 were identified, with serine 125 as the main site for Pin1 binding. As a new Pin1 binding partner, oncogenic PHD2 could be a potential therapeutic target for breast cancer treatment.
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