Upregulated SKP2 Empowers Epidermal Proliferation Through Downregulation of P27 Kip1

Overview

Journal Ann Dermatol

Specialty Dermatology

Date 2024 Sep 29

PMID 39343755

Authors

Lipeng Tang

Bowen Zhang

Guanzhuo Li

Xinmin Qiu

Zixin Dai

Hongying Liu

Ying Zhu

Bing Feng

Zuqing Su

Wenhui Han

Huilin Huang

Qiuping Li

Zihao Zhang

Maojie Wang

Huazhen Liu

Yuchao Chen

Yanmei Zhang

Dinghong Wu

Xirun Zheng

Taohua Liu

Jie Zhao

Chutian Li

Guangjuan Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Excessive growth of keratinocytes is the critical event in the etiology of psoriasis. However, the underlying molecular mechanism of psoriatic keratinocyte hyperproliferation is still unclear.

Objective: This study aimed to figure out the potential contributory role of S-phase kinase-associated protein 2 (SKP2) in promoting the hyperproliferation of keratinocytes in psoriasis.

Methods: We analyzed microarray data (GSE41662) to investigate the gene expression of in psoriatic lesion skins compared with their adjacent non-lesional skin. Then, we further confirmed the mRNA and protein expression of SKP2 in human psoriatic skin tissues, imiquimod (IMQ)-induced psoriatic mice back skins and tumor necrosis factor α (TNF-α), interleukin (IL)-17A and IL-6-stimulated keratinocytes by using real-time quantitative polymerase chain reaction and western blot (WB). Furthermore, we explored the potential pathogenic role and its underlying cellular mechanism of SKP2 in promoting keratinocytes hyperproliferation through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle detection, 5-ethynyl-2'-deoxyuridine staining and WB. Finally, we determined whether inhibition of SKP2 can effectively alleviate the keratinocytes hyperproliferation .

Results: We identified that SKP2 is aberrantly upregulated in the psoriatic lesion skin and cytokines-stimulated keratinocytes. Moreover, upregulated SKP2 augments cytokines-induced keratinocytes hyperproliferation. Mechanistically, enhanced SKP2 increased the S phase ratio through inhibiting Cyclin-Dependent Kinase Inhibitor p27 (P27 Kip1) expression. Correspondingly, suppression of SKP2 with SMIP004 can significantly ease the epidermis hyperplasia .

Conclusion: Our results suggest that elevated SKP2 can empower keratinocytes proliferation and psoriasis-like epidermis hyperplasia via downregulation of P27 Kip1. Therefore, targeting SKP2-P27 Kip1 axis might be a promising therapeutic strategy for the treatment of psoriasis in future.

References

Bigler J, Rand H, Kerkof K, Timour M, Russell C . Cross-study homogeneity of psoriasis gene expression in skin across a large expression range. PLoS One. 2013; 8(1):e52242. PMC: 3537625. DOI: 10.1371/journal.pone.0052242. View

Rico-Bautista E, Yang C, Lu L, Roth G, Wolf D . Chemical genetics approach to restoring p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells. BMC Biol. 2010; 8:153. PMC: 3025922. DOI: 10.1186/1741-7007-8-153. View

Kulinski M, Achkar I, Haris M, Dermime S, Mohammad R, Uddin S . Dysregulated expression of SKP2 and its role in hematological malignancies. Leuk Lymphoma. 2017; 59(5):1051-1063. DOI: 10.1080/10428194.2017.1359740. View

Cui Z, Shen L, Gao X, Dong X, Fu H . S-phase kinase-associated protein-2 (Skp2) promotes nucleus pulposus cell proliferation by inhibition of p27 in attenuating intervertebral disc degeneration. Eur Rev Med Pharmacol Sci. 2020; 24(6):2802-2810. DOI: 10.26355/eurrev_202003_20641. View

Inui N, Sakai S, Kitagawa M . Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway. Int J Mol Sci. 2021; 22(11). PMC: 8201174. DOI: 10.3390/ijms22116107. View

Jeong K, Murphy J, Ahn E, Lim S . FAK in the nucleus prevents VSMC proliferation by promoting p27 and p21 expression via Skp2 degradation. Cardiovasc Res. 2021; 118(4):1150-1163. PMC: 8930076. DOI: 10.1093/cvr/cvab132. View

Wang H, Luo J, Tian X, Xu L, Zhai Z, Cheng M . DNAJC5 promotes hepatocellular carcinoma cells proliferation though regulating SKP2 mediated p27 degradation. Biochim Biophys Acta Mol Cell Res. 2021; 1868(6):118994. DOI: 10.1016/j.bbamcr.2021.118994. View

Zhang T, Yang L, Ke Y, Lei J, Shen S, Shao S . EZH2-dependent epigenetic modulation of histone H3 lysine-27 contributes to psoriasis by promoting keratinocyte proliferation. Cell Death Dis. 2020; 11(10):826. PMC: 7532974. DOI: 10.1038/s41419-020-03028-1. View

Griffiths C, Armstrong A, Gudjonsson J, Barker J . Psoriasis. Lancet. 2021; 397(10281):1301-1315. DOI: 10.1016/S0140-6736(20)32549-6. View

10.

Armstrong A, Read C . Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA. 2020; 323(19):1945-1960. DOI: 10.1001/jama.2020.4006. View

11.

Tang L, Li T, Zhang B, Zhang Z, Sun X, Zhu Y . Punicalagin Alleviates Psoriasis by Inhibiting NF-κB-Mediated IL-1β Transcription and Caspase-1-Regulated IL-1β Secretion. Front Pharmacol. 2022; 13:817526. PMC: 8826397. DOI: 10.3389/fphar.2022.817526. View

12.

Lohmuller M, Roeck B, Szabo T, Schapfl M, Pegka F, Herzog S . The SKP2-p27 axis defines susceptibility to cell death upon CHK1 inhibition. Mol Oncol. 2022; 16(15):2771-2787. PMC: 9348596. DOI: 10.1002/1878-0261.13264. View

13.

Suzuki S, Ohashi N, Kitagawa M . Roles of the Skp2/p27 axis in the progression of chronic nephropathy. Cell Mol Life Sci. 2012; 70(18):3277-87. PMC: 3753466. DOI: 10.1007/s00018-012-1232-x. View

14.

Xia X, Liu X, Chai R, Xu Q, Luo Z, Gu J . USP10 exacerbates neointima formation by stabilizing Skp2 protein in vascular smooth muscle cells. J Biol Chem. 2021; 297(5):101258. PMC: 8524199. DOI: 10.1016/j.jbc.2021.101258. View

15.

Tang L, Zhang B, Li G, Zhu Y, Feng B, Su Z . Punicalagin alleviates the hyperproliferation of keratinocytes in psoriasis through inhibiting SKP2 expression. J Nat Med. 2023; 77(4):712-720. DOI: 10.1007/s11418-023-01711-z. View

16.

Li C, Du L, Ren Y, Liu X, Jiao Q, Cui D . SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination. J Exp Clin Cancer Res. 2019; 38(1):76. PMC: 6375223. DOI: 10.1186/s13046-019-1069-3. View

17.

Adhikary S, Marinoni F, Hock A, Hulleman E, Popov N, Beier R . The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell. 2005; 123(3):409-21. DOI: 10.1016/j.cell.2005.08.016. View

18.

Rioux G, Ridha Z, Simard M, Turgeon F, Guerin S, Pouliot R . Transcriptome Profiling Analyses in Psoriasis: A Dynamic Contribution of Keratinocytes to the Pathogenesis. Genes (Basel). 2020; 11(10). PMC: 7600703. DOI: 10.3390/genes11101155. View

19.

Bochis O, Irimie A, Pichler M, Berindan-Neagoe I . The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer. J Gastrointestin Liver Dis. 2015; 24(2):225-34. DOI: 10.15403/jgld.2014.1121.242.skp2. View

20.

Li F, Huang C, Lu X, Xiang H, Wang D, Chen Z . Identification of the antidepressive properties of C1, a specific inhibitor of Skp2, in mice. Behav Pharmacol. 2021; 32(1):62-72. DOI: 10.1097/FBP.0000000000000604. View