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UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer

Oncogene volume 42, pages 1763–1776 (2023)Cite this article

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Abstract

The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic, pharmacological, and rescue experiments showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. A high level of UBXN2A in patient-derived xenografts and tumor organoids decreases Rictor protein and suppresses the mTORC2 pathway. These findings provide new insights into the functions of an ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.

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Fig. 1: Haploinsufficiency of the UBXN2A tumor suppressor gene promotes colon cancer progression.
Fig. 2: Induction of UBXN2A interferes with the mTORC2 pathway but not the mTORC1 signaling pathway.
Fig. 3: UBXN2A binds to Rictor protein and promotes its proteasomal degradation.
Fig. 4: Absence of UBXN2A leads to elevation of Rictor, resulting in overactivation of mTORC2’s downstream protein targets.
Fig. 5: UBXN2A expression leads to the reduction of VEGF proteins in metastatic colon cancer cells.
Fig. 6: Genetic and pharmacological regulation of UBXN2A suppress colon cancer migration.
Fig. 7: UBXN2A induction decreases cancer stem cell populations in human colon cancer cells.
Fig. 8: UBXN2A protein levels predominantly upgrade during the early stage of tumor development and improve survival rates in colorectal cancer patients.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The DaCCoTA funding is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number U54GM128729 and the National Cancer Institute of the National Institutes of Health under award number 1R03CA223935-01. ARB and the organoid core at UNMC were supported by Nebraska Center for Molecular Target Discovery and Development (P20GM121316) and Fred & Pamela Buffett Cancer Center Support Grant (CA036727). The bioinformatic studies (EGZ) were partially funded by the National Science Foundation/Experimental Program to Stimulate Competitive Research (EPSCoR) Grant OIA-1849206 awarded to Gilbert Ustad and the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health P20GM103443 (V.C.Huber).

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Authors and Affiliations

  1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA

    Sanam Sane, Rekha Srinivasan, Rashaun A. Potts, Morgan Eikanger, Diana Zagirova, Jessica Freeling, Casey A. Reihe, Ryan M. Antony, Brij K. Gupta & Khosrow Rezvani

  2. Laboratory Medicine and Pathology, Sanford School of Medicine, Sioux Falls, SD, USA

    Douglas Lynch

  3. Sanford Cancer Center, Sioux Falls, SD, USA

    Jonathan Bleeker

  4. Sanford Surgical Associates, Sioux Falls, SD, USA

    Hassan Turaihi

  5. Veterinary and Biomedical Sciences Department, Animal Disease Research and Diagnostic Laboratory, South Dakota State University, Brookings, SD, USA

    Angela Pillatzki

  6. Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Wei Zhou

  7. Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, The University of Nebraska Medical Center, Omaha, NE, USA

    Xu Luo

  8. Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock, Germany

    Michael Linnebacher

  9. Biomedical Engineering Department, GEAR Center, Sioux Falls, SD, USA

    Diing Agany & Etienne Gnimpieba Zohim

  10. Tissue Sciences, Eppley Institute for Cancer Research, The University of Nebraska Medical Center, Omaha, NE, USA

    Lisa E. Humphrey & Adrian R. Black

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  18. Etienne Gnimpieba Zohim
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  19. Lisa E. Humphrey
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  20. Adrian R. Black
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  21. Khosrow Rezvani
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Contributions

All authors contributed to designing, performing, or analyzing the experiments. The work was supervised by KR, and KR wrote the manuscript. All authors took part in editing the manuscript.

Corresponding author

Correspondence to Khosrow Rezvani.

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Competing interests

The authors declare no competing interests.

Ethical approval

The use of archived clinical samples in this study was approved by the institutional review board (IRB) at Sanford Research/USD, Sioux Falls, South Dakota. All animal procedures were approved by the Institutional Animal Care and Use Committee by federal guidelines (the University of South Dakota-IACUC#04-03-20-23E).

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Sane, S., Srinivasan, R., Potts, R.A. et al. UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer. Oncogene 42, 1763–1776 (2023). https://doi.org/10.1038/s41388-023-02686-7

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  • DOI: https://doi.org/10.1038/s41388-023-02686-7

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