Improving The Anti-tumor Effect Of EGCG In Colorectal Cancer Cells By Blocking EGCG-induced YAP Activation

EGCG also known as epigallocatechin gallate,is the main active ingredient in green tea and can effectively interact with colorectal epithelial cells or colorectal cancer cells.The preventive or anti-colorectal cancer effect of EGCG has been well characterized in preclinical trials.The anti-tumor effect of EGCG is benefited from several aspects.First,EGCG can inhibit the proliferation of colorectal cancer cells,causing the cancer cell cycle to stall or slow down,thus slowing down the growth rate of cancer cells.Second,EGCG can promote cell apoptosis,thus causing the death of cancer cells.Third,EGCG can inhibit the invasion and metastasis of colorectal cancer cells,thus reducing the destruction and spread of cancer cells to surrounding tissues and organs.However,due to the rapid metabolism,low bioavailability and high toxicity of EGCG and its derivatives,the clinical efficacy of EGCG is limited.Therefore,how to improve the antitumor effect of EGCG has become an open question.Our results suggested that in colorectal cancer cell lines,EGCG treatment can inhibit Hippo signaling pathway and compensatively activate downstream YAP protein activity to antagonize the therapeutic effect of EGCG.Inhibition of YAP activity can effectively restore the sensitivity of colorectal cancer cells to EGCG therapy.The main findings are as follows:1.In various colorectal cell lines,EGCG treatment downregulated LATS1/2 protein homeostasis through a ubiquitin proteasome dependent pathway.2.EGCG treatment activated the activity of chaperone HSP90 cofactor CHIP,which mediated their ubiquitination and degradation through interaction with LATS1/2 protein.3.In colorectal cancer cell lines,EGCG can be promoted YAP protein stability,low phosphorylation,nuclear localization and transcriptional activation of downstream target genes CTGF,CYR61 and ANKRD1.4.Activated YAP can be antagonized the therapeutic effect of EGCG by inducing originally retarded cancer cells to reenter the cell cycle.Knockout of YAP in colorectal cancer cells would increased the antitumor effect of EGCG.