Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer.

Xuan Zhang,Yifei Li,Aibei Du,Qing Shi,Yang Zhao,Qing Li,Feng Pan,Bin Wang,Yanrong Chen

doi:10.3389/fonc.2021.748730

Abstract

The development of resistance to 5-fluorouracil (5FU) chemotherapy is a major handicap for sustained effective treatment in peritoneal carcinomatosis (PC) of colorectal cancer (CRC). Metabolic reprogramming of adipocytes, a component of the tumor microenvironment and the main composition of peritoneum, plays a significant role in drug resistance of PC, with the mechanisms being not fully understood. By performing metabolomics analysis, we identified glutamine (Gln), an important amino acid, inducing resistance to 5FU-triggered tumor suppression of CRC-PC through activating mTOR pathway. Noteworthily, genetic overexpression of glutamine synthetase (GS) in adipocytes increased chemoresistance to 5FU in vitro and in vivo while this effect was reversed by pharmacological blockage of GS. Next, we showed that methionine metabolism were enhanced in amino acid omitted from CRC-PC of GS transgenic (TgGS) mice, increasing intracellular levels of S-carboxymethy-L-cys. Moreover, loss of dimethylation at lysine 4 of histone H3 (H3k4me2) was found in adipocytes in vitro, which may lead to increased expression of GS. Furthermore, biochemical inhibition of lysine specific demethylase 1 (LSD1) restored H3k4me2, thereby reducing GS-induced chemoresistance to 5FU. Our findings indicate that GS upregulation-induced excessive of Gln in adipocytes via altered histone methylation is potential mediator of resistance to 5FU chemotherapy in patients with CRC-PC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancers and the fourth leading cause of cancer-associated mortality worldwide [1, 2]
These results suggest that adipocytes induce chemoresistance to 5FU treatment for CRC
Our present study reveals a novel mechanism of chemoresistance of CRC-peritoneal carcinomatosis (PC) to 5FU therapy

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancers and the fourth leading cause of cancer-associated mortality worldwide [1, 2]. Metastasis is the main cause of poor outcome in CRC patients. PC is a well-known indicator of poor prognosis of CRC, and the median survival time of patients with PC is only 6–11 months [4, 5]. Resistance to 5FU treatment in patients with CRC remains common, promoting tumor recurrence and metastasis [9], with the mechanisms being not fully known. It is crucial to get a better understanding of the underlying mechanisms of resistance to 5FU chemotherapy for the management of patients with CRC- PC

Methods

Results

Conclusion