The HP1-PEPCK axis suppresses the HDS-induced tumor progression

Abstract

High-dietary-sugar (HDS) induces metabolic diseases and aggravates tumor progression through upregulating Wingless/Wnt signaling It has been shown that levels of heterochromatin protein 1 (HP1) a key epigenetic molecule of heterochromatin formation associated with histone 3 lysine 9 methylation including dimethylation (H3K9me2) are decreased in various human cancers Unpublished data in our lab have found that HP1 reduces HDS-induced Drosophila tumor progression likely via regulating metabolism-related genes including phosphoenolpyruvate carboxykinase (pepck) PEPCKs including PEPCK1 and PEPCK2 have been shown to promote tumor growth by reorganizing metabolic processes However the molecular mechanism by which HP1-PEPCK axis mediates the progression of HDS-induced tumor remains unclear Thus I hypothesize that the HP1-PEPCK axis inhibits the HDS-induced tumor progression through heterochromatin-mediated pepcks downregulation Here we find that HP1-mediated heterochromatin directly interacts with the pepck1 gene as shown by the ChIP assay with an anti-H3K9me2 antibody in flies overexpressing HP1 Furthermore overexpression of HP1 reduces pepck1 expression in HDS-induced tumor tissues in Drosophila K-Ras/Src tumor models pepck1/2 are upregulated during HDS-induced tumor progression Moreover pepck1/2 knockdown reduces tumor size and increases animal survival in HDS-induced tumor animals Importantly knockdown of pepck1/2 decreases Wingless/dWnt-signaling and increases genome stability in HDS-induced tumor cells Taken together these results suggest that the HP1-PEPCK axis inhibits the HDS-induced tumor progression via heterochromatin-mediated direct downregulation of pepcks Our research reveals epigenetically regulated metabolic targets for developing more effective cancer therapy

Date of Award	2019
Original language	English
Supervisor	Shian-Jang Yan (Supervisor)