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 in epidemiological and laboratory studies. Although it has been reported that fructose promotes cancer development and progression, little is known about the underlying molecular 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. An orthotopic xenograft experiment revealed that ketohexokinase16 A-overexpressing breast cancer is highly metastatic in fructose-fed mice. Mechanistically, ketohexokinase-A moves from the cytoplasm to the nucleus during fructose stimulation, which is mediated by the nuclear importers LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and, in turn, YWHAH recruits SLUG to the CDH1 promoter, 20 which weakens cell adhesion and triggers cell migration. This study provides a new insight into 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Breast Cancer

SUBMITTER: Jongmin Woo  

LAB HEAD: Jongmin Woo

PROVIDER: PXD021035 | Pride | 2020-11-09

REPOSITORIES: Pride