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.