Serine Metabolism Regulates YAP Activity Through USP7 in Colon Cancer.

Xiaoya Zhao,Lude Wang,Jinlin Du,Lin Chen,Wenxia Xu,Jing Wang,Chenyang Ge,Jianfei Fu,Bin Hu,Jinyong Fang,Haiping Lin,Kailing Pan,Liang Fu

doi:10.3389/fcell.2021.639111

Abstract

Metabolic reprogramming is a vital factor in the development of many types of cancer, including colon cancer. Serine metabolic reprogramming is a major feature of tumor metabolism. Yes-associated protein (YAP) participates in organ size control and tumorigenesis. However, the relationship between YAP and serine metabolism in colon cancer is unclear. In this study, RNA sequencing and metabolomics analyses indicated significant enrichment of the glycine, serine, and threonine metabolism pathways in serine starvation–resistant cells. Short-term serine deficiency inhibited YAP activation, whereas a prolonged response dephosphorylated YAP and promoted its activity. Mechanistically, USP7 increases YAP stability under increased serine conditions by regulating deubiquitination. Verteporfin (VP) effectively inhibited the proliferation of colon cancer cells and organoids and could even modulate serine metabolism by inhibiting USP7 expression. Clinically, YAP was significantly activated in colon tumor tissues and positively correlated with the expression of phosphoglycerate dehydrogenase (PHGDH) and USP7. Generally, our study uncovered the mechanism by which serine metabolism regulates YAP via USP7 and identified the crucial role of YAP in the regulation of cell proliferation and tumor growth; thus, VP may be a new treatment for colon cancer.

Highlights

Colon cancer, a malignant tumor of the colon, is often associated with rectal cancer; it is often called colorectal cancer (CRC)
We found that the proliferation ability of cells obtained from long-term exogenous serine deprivation was stronger than that of parental cells (Figure 1C), suggesting that these cells were resistant to serine deprivation
Our results provide the first indication that the activity of synthesis pathway (SSP) and the Hippo signaling pathway were increased in cells in response to long-term serine deficiency

Summary

Introduction

A malignant tumor of the colon, is often associated with rectal cancer; it is often called colorectal cancer (CRC). Knowledge of the mechanism of the occurrence and development of colon cancer should provide a scientific basis to identify effective prevention and treatment strategies. Nutrition plays both causal and protective roles in the development of colon cancer (Thanikachalam and Khan, 2019). The regulatory mechanism behind the altered serine metabolism in colon cancer remains incompletely understood, and the relationship between serine metabolic/mechanistic dysregulation and tumor growth is not well characterized

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