TRC8 suppresses tumorigenesis through targeting heme oxygenase-1 for ubiquitination and degradation.
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.
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
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PH
Lin
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WM
Lan
L-Y
LY
Chau
D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D059565:G2 Phase Cell Cycle Checkpoints; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C114025:RNF139 protein, human; D011956:Receptors, Cell Surface; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1