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SENP1 promotes p27kip1 nuclear export though enhanced SUMOylation in cholangiocarcinoma leading to increased cell proliferation and chemoresistance

  • Authors:
    • Kainian Jiang
    • Wei Yang
    • Jie Huang
    • Xiaolong Tan
    • Yan Liu
    • Saiya Tu
    • Jian Luo

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  • Published online on: July 11, 2025     https://doi.org/10.3892/ijmm.2025.5582
  • Article Number: 141

  • Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

SUMOylation is a critical post‑translational modification, serving as a key role in nucleocytoplasmic translocation, transcriptional cofactor stabilization and modulation of chromatin remodeling factors, which are associated with oncogenesis, tumor progression and chemotherapy resistance in various types of cancer. SUMOylation was performed by small ubiquitin‑like modifier (SUMO), a kind of small ubiquitin‑like modifier, which was attached or removed from the substrates. The excessive export of nuclear p27kip1 induced by SUMOylation is associated with cell proliferation and chemotherapy resistance in cholangiocarcinoma (CCA). However, the exact underlying mechanism remains currently unknown. The present study investigated SUMO specific peptidase 1 (SENP1), which is known to participate in SUMOylation by activating nuclear SUMO1 precursors and deSUMOylating cytoplasmic substrates. SENP1 exhibited increased expression levels in CCA specimens compared with that in adjacent non‑cancerous tissues, as confirmed by bioinformatics analysis and immunohistochemical assays. A significant correlation between SENP1 and p27kip1 expression levels was observed. SENP1 overexpression significantly increased cytoplasmic p27kip1 expression levels, thereby promoting CCA cell proliferation, accelerating the G1‑S cell cycle transition and reducing chemical sensitivity through increasing overall SUMOylation of p27kip1, as confirmed via western blotting, immunofluorescence, flow cytometry, Cell Counting Kit‑8, 5‑ethynyl‑2'‑deoxyuridine incorporation and SUMOylation tests. By contrast, SENP1 knockdown demonstrated the opposite results. Subsequently, the use of ML‑792, COH000 and leptomycin B treatments, and the mutant variant SENP1‑C603A demonstrated that SENP1 regulates the functionality of p27kip1 through nuclear SUMOylation rather than cytoplasmic deSUMOylation. The involvement of SENP1 represents a pivotal role in governing the nucleocytoplasmic shuttling of p27kip1. SENP1 knockdown could effectively impede CCA cell proliferation and enhance the chemosensitivity of cis‑platinum by modulating the nuclear export of p27kip1 through SUMOylation, thus offering a potential therapeutic approach for CCA in the future.
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September-2025
Volume 56 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Jiang K, Yang W, Huang J, Tan X, Liu Y, Tu S and Luo J: SENP1 promotes p27kip1 nuclear export though enhanced SUMOylation in cholangiocarcinoma leading to increased cell proliferation and chemoresistance. Int J Mol Med 56: 141, 2025.
APA
Jiang, K., Yang, W., Huang, J., Tan, X., Liu, Y., Tu, S., & Luo, J. (2025). SENP1 promotes p27kip1 nuclear export though enhanced SUMOylation in cholangiocarcinoma leading to increased cell proliferation and chemoresistance. International Journal of Molecular Medicine, 56, 141. https://doi.org/10.3892/ijmm.2025.5582
MLA
Jiang, K., Yang, W., Huang, J., Tan, X., Liu, Y., Tu, S., Luo, J."SENP1 promotes p27kip1 nuclear export though enhanced SUMOylation in cholangiocarcinoma leading to increased cell proliferation and chemoresistance". International Journal of Molecular Medicine 56.3 (2025): 141.
Chicago
Jiang, K., Yang, W., Huang, J., Tan, X., Liu, Y., Tu, S., Luo, J."SENP1 promotes p27kip1 nuclear export though enhanced SUMOylation in cholangiocarcinoma leading to increased cell proliferation and chemoresistance". International Journal of Molecular Medicine 56, no. 3 (2025): 141. https://doi.org/10.3892/ijmm.2025.5582