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TRC8 suppresses tumorigenesis through targeting heme oxygenase-1 for ubiquitination and degradation

Oncogene volume 32, pages 2325–2334 (2013)Cite this article

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Abstract

The TRC8 gene, which was previously shown to be disrupted by a 3;8 chromosomal translocation in hereditary kidney cancer, encodes for an endoplasmic reticulum-resident E3 ligase. Studies have shown that TRC8 exhibits a tumor-suppressive effect through its E3-ligase activity. Therefore, the identification of its physiological substrates will provide important insights into the molecular mechanism underlying TRC8-mediated tumor suppression. Here we show that TRC8 targets heme oxygenase-1 (HO-1), an antioxidant enzyme highly expressed in various cancers, for ubiquitination and degradation. Ectopic TRC8 expression suppresses HO-1-induced cancer cell growth and migration/invasion. Conversely, HO-1 depletion reduced the tumorigenic and invasive capacities promoted by TRC8 knockdown. HO-1 downregulation in renal carcinoma cells induces a mitotic delay at G2/M phase by increasing the intracellular reactive oxygen species and the DNA-damage-induced checkpoint activation. These results highlight the tumorigenic role of HO-1 and the importance of TRC8-mediated HO-1 degradation in the control of cancer growth.

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Acknowledgements

This work was supported by an Academia Sinica Investigatorship to LYC and a grant from the National Science Council of Taiwan (NSC 100-2320-B-100-009MY3).

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Authors and Affiliations

  1. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC

    P-H Lin, W-M Lan & L-Y Chau

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC

    P-H Lin, W-M Lan & L-Y Chau

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Correspondence to L-Y Chau.

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Lin, PH., Lan, WM. & Chau, LY. TRC8 suppresses tumorigenesis through targeting heme oxygenase-1 for ubiquitination and degradation. Oncogene 32, 2325–2334 (2013). https://doi.org/10.1038/onc.2012.244

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