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

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.
Authors	Jiyoung Kim, Jengmin Kang, Ye-Lim Kang, Jongmin Woo, Youngsoo Kim, June Huh, Jong-Wan Park
Journal	Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 5436 (10 28 2020) ISSN: 2041-1723 [Electronic] England
PMID	33116123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	14-3-3 Proteins Carcinogens KPNB1 protein, human LRRC59 protein, human Membrane Proteins YWHAH protein, human beta Karyopherins Fructose Fructokinases ketohexokinase
Topics	14-3-3 Proteins (antagonists & inhibitors, genetics, metabolism) Animals Breast Neoplasms (metabolism, pathology) Carcinogens (administration & dosage, metabolism) Cell Line, Tumor Cell Nucleus (metabolism) Female Fructokinases (metabolism) Fructose (administration & dosage, metabolism) Gene Knockdown Techniques Humans Mammary Neoplasms, Experimental (metabolism, pathology) Membrane Proteins (antagonists & inhibitors, genetics, metabolism) Mice Neoplasm Invasiveness (pathology) Neoplasm Metastasis (pathology) Phosphorylation Signal Transduction beta Karyopherins (metabolism)

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