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Abstract

Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the ACOT family that catalyzes hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH. However, canonical and non-canonical functions of ACOT7 remain to be discovered. In this study, for the first time, ACOT7 was shown to be responsive to genotoxic stresses such as ionizing radiation (IR) and the anti-cancer drug doxorubicin in time- and dose-dependent manners. ACOT7 knockdown induced cytostasis via activation of the p53-p21 signaling pathway without a DNA damage response. PKCζ was specifically involved in ACOT7 depletion-mediated cell cycle arrest as an upstream molecule of the p53-p21 signaling pathway in MCF7 human breast carcinoma and A549 human lung carcinoma cells. Of the other members of the ACOT family, including ACOT1, 4, 8, 9, 11, 12, and 13 that were expressed in human, ACOT4, 8, and 12 were responsive to genotoxic stresses. However, none of those had a role in cytostasis via activation of the PKCζ-p53-p21 signaling pathway. Analysis of the ACOT7 prognostic value revealed that low ACOT7 levels prolonged overall survival periods in breast and lung cancer patients. Furthermore, ACOT7 mRNA levels were higher in lung cancer patient tissues compared to normal tissues. We also observed a synergistic effect of ACOT7 depletion in combination with either IR or doxorubicin on cell proliferation in breast and lung cancer cells. Together, our data suggest that a low level of ACOT7 may be involved, at least in part, in the prevention of human breast and lung cancer development via regulation of cell cycle progression.

Author information

Jung SH1,2, Lee HC1,2, Hwang HJ1,2, Park HA1, Moon YA1, Kim BC3, Lee HM4, Kim KP4, Kim YN5, Lee BL6, Lee JC7, Ko YG8, Park HJ2,9, Lee JS1,2.​

1Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.2Hypoxia-Related Disease Research Center, Inha University College of Medicine, Incheon, Korea.3Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.4Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Korea.5Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Korea.6Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea.7Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.8Division of Life Sciences, Korea University, Seoul, Korea.9Department of Microbiology, Inha University College of Medicine, Incheon, Korea.