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

Jiyoung Kim, Jengmin Kang, Ye-Lim Kang, Jongmin Woo, Youngsoo Kim, June Huh and Jong-Wan Park ()
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Jiyoung Kim: Seoul National University College of Medicine
Jengmin Kang: Seoul National University College of Medicine
Ye-Lim Kang: Seoul National University College of Medicine
Jongmin Woo: Seoul National University College of Medicine
Youngsoo Kim: Seoul National University College of Medicine
June Huh: Korea University
Jong-Wan Park: Seoul National University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19263-1

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