Cellular stresses initiate well-coordinated signaling response pathways. As the proper regulation of stress is essential for cellular homeostasis, the defects of stress response pathways result in functional deficits and cell death. Although mitochondrial SIRT4 has been shown to be involved in cellular stress response and tumor suppression, its roles in survival and drug resistance of cancer cells are not well determined. Here we show that SIRT4 is a crucial regulator of the stress resistance of cancer cells. SIRT4 is highly induced by various cellular stresses and contributes to cell survival and growth after stresses. SIRT4 loss sensitizes cells to DNA damage or ER stress. Moreover, SIRT4 induction is required for tumorigenic transformation, as SIRT4 null cells are vulnerable to oncogene activation. Thus, these results suggest that SIRT4 has essential roles in stress resistance and may be an important therapeutic target for cancer treatment. (C) 2016 Elsevier Inc. All rights reserved.