2. Academic Validation
  3. Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer

Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer

  • Nat Commun. 2020 Oct 28;11(1):5436. doi: 10.1038/s41467-020-19263-1.
Jiyoung Kim 1 2 3,  Jengmin Kang 1 2 3,  Ye-Lim Kang 1 2,  Jongmin Woo 2,  Youngsoo Kim 2 4,  June Huh 5,  Jong-Wan Park 6 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
  • 2 Department of Biomedical Science, BK21-plus education program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
  • 3 Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
  • 4 Department of Biomedical Engineering, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
  • 5 Department of Chemical and Biological Engineering, Korea University, Anam-ro, Seongbuk-gu, Seoul, 02841, Korea.
  • 6 Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. parkjw@snu.ac.kr.
  • 7 Department of Biomedical Science, BK21-plus education program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. parkjw@snu.ac.kr.
  • 8 Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. parkjw@snu.ac.kr.
PMID: 33116123 DOI: 10.1038/s41467-020-19263-1
Abstract

Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote Cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast Cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast Cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast Cancer metastasis. High intake of fructose should be restricted in Cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent Cancer metastasis.

Figures