Journal of Pharmacological Sciences (Jan 2020)

β-Hydroxybutyrate enhances the cytotoxic effect of cisplatin via the inhibition of HDAC/survivin axis in human hepatocellular carcinoma cells

  • Daisuke Mikami,
  • Mamiko Kobayashi,
  • Junsuke Uwada,
  • Takashi Yazawa,
  • Kazuko Kamiyama,
  • Kazuhisa Nishimori,
  • Yudai Nishikawa,
  • Sho Nishikawa,
  • Seiji Yokoi,
  • Takanobu Taniguchi,
  • Masayuki Iwano

DOI
https://doi.org/10.1016/j.jphs.2019.10.007
Journal volume & issue
Vol. 142, no. 1
pp. 1 – 8

Abstract

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Ketone bodies, including acetoacetate and β-hydroxybutyrate (βOHB), are produced from acetyl coenzyme A in the liver and then secreted into the blood. These molecules are a source of energy for peripheral tissues during exercise or fasting. βOHB has been reported to inhibit histone deacetylases (HDACs) 1, 3, and 4 in human embryonic kidney 293 cells. Thus, βOHB may regulate epigenetics by modulating HDACs. There have been several reports that the administration of βOHB or induction of a physiological state of ketosis has an antitumor effect; however, the mechanism remains unclear. The aim of this study was to investigate whether βOHB enhances cisplatin-induced apoptosis in hepatocellular carcinoma (HCC) cells by modulating activity and/or expression of HDACs. We found that βOHB significantly enhanced cisplatin-induced apoptosis and cleavage of caspase-3 and -8 in HCC cells. Further, βOHB significantly decreased the expression of HDCA 3/5/6 and survivin in liver hepatocellular (HepG2) cells. In HDAC3/6 gene silencing, survivin expression was significantly decreased, and cisplatin-induced cleavage of caspase-3 was significantly enhanced compared with control in HepG2 cells. In conclusion, βOHB enhanced cisplatin-induced apoptosis via HDAC3/6 inhibition/survivin axis in HepG2 cells, which suggests that βOHB could be a new adjuvant agent for cisplatin chemotherapy. Keywords: Ketone body, β-Hydroxybutyrate, Histone deacetylase, Apoptosis, Survivin