TC1 (C8orf4) is associated with aggressive behavior and poor survival in cancer. We have recently reported that it is a target gene of NF-kappaB and regulates the Wnt/beta-catenin pathway. Here, we show that TC1 is upregulated by various cellular stresses and mediates heat shock response. Heat shock and other cellular stresses including H2O2, 12-O-tetradecanoylphorbol 13-acetate (TPA), lipopolysaccharide (LPS), and UV enhance TC1 transcription in HeLa, KATO-III, HEK293T, and HK cells. TC1 protein then moves into the nuclei independently of NF-kappaB activation. TC1 upregulates heat shock proteins, and TC1-knockdown inhibits stress-induced downstream regulation significantly. Heat shock factor 1(HSF1) and TC1 upregulate each other, suggesting a potential positive feedback in the heat shock response regulation. Our data suggest that TC1 is a novel heat shock response regulator.