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E3 ubiquitin ligases in cancer stem cells: key regulators of cancer hallmarks and novel therapeutic opportunities

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Abstract

Background

Human malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination.

Conclusion

In this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine.

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Acknowledgements

We thank all the members in the laboratory for helpful discussions on the manuscript.

Funding

This work was supported by the National Key Research and Development Program of China (No. 2022YFA1105300 to Bin Wang), National Natural Science Foundation of China (NSFC Nos. 81872027, 91959111, and 81822032 to Bin Wang), Natural Science Foundation of Chongqing (No. CSTC2019JCYJJQX0027 to Bin Wang), Medical Scientific Research Project of Chongqing Medical and Health Committee (2018GDRC006 to Yi Zhang), Funding from the Jin Feng laboratory to Bin Wang, and Funding from the Army Medical University (Nos. 2019CXLCA001, 2018XLC2023, and 2019XQY19 to Bin Wang), the National Institutes of Health, USA (R01AG077574), Nebraska Department of Health & Human Services (DHHS) LB595, LB606, and Creighton University startup funds (LB692) to Brian North. Through LB595, LB606 and LB692, this work is supported by revenue from Nebraska’s excise tax on cigarettes awarded to Brian North of Creighton University through the Nebraska Department of Health & Human Services (DHHS). Its contents represent the view(s) of the author(s) and do not necessarily represent the official views of the State of Nebraska or DHHS.

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Authors and Affiliations

  1. Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, People’s Republic of China

    Qiang Zou & Yi Zhang

  2. Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People’s Republic of China

    Qiang Zou, Meng Liu, Kewei Liu & Bin Wang

  3. Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing University Medical School, Chongqing, 400030, People’s Republic of China

    Meng Liu

  4. Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, 68178, USA

    Brian J. North

  5. Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China

    Bin Wang

  6. Jinfeng Laboratory, Chongqing, 401329, People’s Republic of China

    Bin Wang

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  1. Qiang Zou
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Contributions

Qiang Zou with the assistance of Meng Liu collected all the reference, made the table, and wrote the manuscript draft. Qiang Zou and Yi Zhang designed and drawn all the figures. Brian J. North checked the structure and grammar. Bin Wang discussed and amended the manuscript. Bin Wang, Brian J. North and Yi Zhang supervised the whole process. Bin Wang and Brian J. North edited the manuscript and approved the submission. All the authors contributed to the final version of the manuscript.

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Correspondence to Yi Zhang, Brian J. North or Bin Wang.

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Qiang Zou and Meng Liu share co-first authorship.

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Zou, Q., Liu, M., Liu, K. et al. E3 ubiquitin ligases in cancer stem cells: key regulators of cancer hallmarks and novel therapeutic opportunities. Cell Oncol. 46, 545–570 (2023). https://doi.org/10.1007/s13402-023-00777-x

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