Abstract
Cancer cell stemness contributes significantly to intrahepatic cholangiocarcinoma (ICC) progression. However, the roles of deubiquitinating enzymes (DUBs) in ICC modulation are poorly understood. Ubiquitin specific peptidase 10 (USP10) was highly expressed in ICC spheres. The interaction between USP10 and snail family transcriptional repressor 1 (SNAI1) reduced the polyubiquitination of the SNAI1 protein and stabilized the SNAI1 protein. USP10 knockdown in RBE cells inhibited cell proliferation, promoted cell apoptosis and decreased the diameter of the formed spheres and the expression levels of CD44, EpCAM, OCT4 and SOX2. SNAI1 overexpression alleviated the effect of USP10 knockdown in RBE cells. In addition, the knockdown of USP10 attenuated the ability of RBE cells to form tumors subcutaneously in nude mice. Our results revealed that USP10 attenuates ICC cell malignancy by deubiquitinating SNAI1, indicating that USP10 could be developed as a therapeutic target for ICC treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, Conner EA, Gillen MC, Roskams T, Roberts LR, Factor VM, Thorgeirsson SS (2012) Genomic and genetic characterization of Cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142:1021–U1552
Badarinath K, Dam B, Kataria S, Zirmire RK, Dey R, Kansagara G, Ajnabi J, Hegde A, Singh R, Masudi T, Sambath J, Sachithanandan SP, Kumar P, Gulyani A, He YW, Krishna S, Jamora C (2022) Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin. Cell Rep 40:111390
Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134
Bhattacharya U, Thavathiru E, Neizer-Ashun F, Xu C, Gatalica Z, Dwivedi SKD, Dey A, Mukherjee P, Bhattacharya R (2022) The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress. NPJ Precis Oncol 6:93
Cabrera MC, Hollingsworth RE, Hurt EM (2015) Cancer stem cell plasticity and tumor hierarchy. World J Stem Cells 7:27–36
Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A 108:7950–7955
Chen S, Liu Y, Zhou H (2021) Advances in the development ubiquitin-specific peptidase (USP) inhibitors. Int J Mol Sci 22:4546
DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ, Schulick RD (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245:755–762
Dodson RM, Weiss MJ, Cosgrove D, Herman JM, Kamel I, Anders R, Geschwind JF, Pawlik TM (2013) Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 217:736–750 e734
Fabregat I, Malfettone A, Soukupova J (2016) New Insights into the crossroads between EMT and stemness in the Context of Cancer. J Clin Med 5:37
Galvagni F, Neri F (2015) Snai1 represses nanog to promote embryonic stem cell differentiation. Genom Data 4:82–83
He Y, Jiang S, Mao C, Zheng H, Cao B, Zhang Z, Zhao J, Zeng Y, Mao X (2021) The deubiquitinase USP10 restores PTEN activity and inhibits non-small cell lung cancer cell proliferation. J Biol Chem 297:101088
Hershko A (1983) Ubiquitin: roles in protein modification and breakdown. Cell 34:11–12
Jiang L, Shen J, Zhang N, He Y, Wan Z (2021) Association of RGS20 expression with the progression and prognosis of renal cell carcinoma. Oncol Lett 22:643
Johnston SC, Riddle SM, Cohen RE, Hill CP (1999) Structural basis for the specificity of ubiquitin C-terminal hydrolases. EMBO J 18:3877–3887
Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H (2000) Incidence of primary cholangiocellular carcinoma of the liver in japanese patients with hepatitis C virus-related cirrhosis. Cancer 88:2471–2477
Maithel SK, Gamblin TC, Kamel I, Corona-Villalobos CP, Thomas M, Pawlik TM (2013) Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer 119:3929–3942
Matsui WH (2016) Cancer stem cell signaling pathways. Med (Baltim) 95:S8–S19
Mortezaee K, Majidpoor J, Kharazinejad E (2022) Epithelial-mesenchymal transition in cancer stemness and heterogeneity: updated. Med Oncol 39:193
Quan G, Xu J, Wang J, Liu X, Xu J, Jiang J (2023) KIF15 is essential for USP10-mediated PGK1 deubiquitination during the glycolysis of pancreatic cancer. Cell Death Dis 14:137
Shaib YH, Davila JA, McGlynn K, El-Serag HB (2004) Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 40:472–477
Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA (2005) Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 128:620–626
Shi J, Zhang Q, Yin X, Ye J, Gao S, Chen C, Yang Y, Wu B, Fu Y, Zhang H, Wang Z, Wang B, Zhu Y, Wu H, Yao Y, Xu G, Wang Q, Wang S, Zhang W (2023) Stabilization of IGF2BP1 by USP10 promotes breast cancer metastasis via CPT1A in an m6A-dependent manner. Int J Biol Sci 19:449–464
Swatek KN, Komander D (2016) Ubiquitin modifications. Cell Res 26:399–422
Tao L, Liu X, Jiang X, Zhang K, Wang Y, Li X, Jiang S, Han T (2022) USP10 as a potential therapeutic target in human cancers. Genes (Basel) 13:831
Tracz M, Bialek W (2021) Beyond K48 and K63: non-canonical protein ubiquitination. Cell Mol Biol Lett 26:1
Tsirigoti C, Ali MM, Maturi V, Heldin CH, Moustakas A (2022) Loss of SNAI1 induces cellular plasticity in invasive triple-negative breast cancer cells. Cell Death Dis 13:832
Zou S, Li J, Zhou H, Frech C, Jiang X, Chu JS, Zhao X, Li Y, Li Q, Wang H, Hu J, Kong G, Wu M, Ding C, Chen N, Hu H (2014) Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 5:5696
Acknowledgements
We appreciate the support of the Medical and Health Science and Technology Project of Zhejiang Province.
Funding
This study was supported by the Medical and Health Science and Technology Project of Zhejiang Province (2021447209).
Author information
Authors and Affiliations
Contributions
WZ and YL designed this study. WZ, BY, SY, and YL performed the experiments and analyzed the results. WZ and BY wrote the manuscript. SY and YL revised the manuscript. All the authors approved the version to be published. They agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part were appropriately investigated and resolved.
Corresponding author
Ethics declarations
Competing interests
No benefits in any form have been received or will be received from a commercial party directly or indirectly related to the subject of this article.
Ethical approval
This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhu, W., Ye, B., Yang, S. et al. USP10 promotes intrahepatic cholangiocarcinoma cell survival and stemness via SNAI1 deubiquitination. J Mol Histol 54, 703–714 (2023). https://doi.org/10.1007/s10735-023-10150-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-023-10150-9