FATS regulates polyamine biosynthesis by promoting ODC degradation in an ER\u03b2-dependent manner in non-small-cell lung cancer

Li Qiu,Xianhui Ruan,Huijuan Wang,Pengzhou Kong,Linfei Hu,Xiangqian Zheng,Jun Zhang,Jinling Li,Ming Gao,Lin Gu,Jingtai Zhi,Bingsheng Sun

doi:10.1038/s41419-020-03052-1

Abstract

Polyamine biosynthesis is an essential metabolic pathway for cell growth and differentiation in non-small-cell lung cancer (NSCLC). Fragile-site associated tumour suppressor (FATS) is a novel gene involved in cancer. The results of our previous study showed that FATS-mediated polyubiquitination of p53 promotes the activation of p53 in response to DNA damage; however, little is known about the role of FATS in metabolic reprogramming in NSCLC. In the present study, FATS was observed to be significantly downregulated in NSCLC tissues compared with paired adjacent normal tissues and was associated with the survival of NSCLC patients. We further showed that the presence of the tumour suppressor FATS in NSCLC cells led to apoptosis by inducing pro-death autophagy. In addition, FATS was shown to function as a suppressor of polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) at the protein and mRNA levels, which was partially dependent on oestrogen receptor (ER). Furthermore, FATS was observed to bind to ERβ and translocate to the cytosol, leading to ODC degradation. The findings of our study demonstrate that FATS plays important roles in polyamine metabolism in NSCLC and provides a new perspective for NSCLC progression.

Highlights

To maintain their growth, cancer cells need to constantly obtain nutrients, including amino acids, nucleic acids and fatty acids, through external intake or selfsynthesis[1] and require that metabolism inside cells be maintained in a balanced state[2]
To tumour progression, Fragile-site associated tumour suppressor (FATS) was overexpressed via transfection with a p3×Flag-FATS overexpression plasmid in A549, H520, H358 and H460 cells (Fig. 2a and S1A), Fig. 1 FATS is associated with non-small-cell lung cancer (NSCLC) progression and patient survival. a RT-qPCR results of FATS mRNA levels in NSCLC patients and adjacent normal lung tissues (n = 20). b, c FATS protein levels in NSCLC patients and paired normal tissue samples (n = 14) analysed by western blotting
The functions of FATS in regulating p53 in ubiquitin signalling were reported in our previous study[16], the roles of this oncogene in apoptosis or metabolism have remained unknown

Summary

Introduction

Cancer cells need to constantly obtain nutrients, including amino acids, nucleic acids and fatty acids, through external intake or selfsynthesis[1] and require that metabolism inside cells be maintained in a balanced state[2]. Introducing an additional substance or an abnormal supply of nutrients will disturb this balance, causing an altered growth state of cells and leading to apoptosis or autophagy[3]. Apoptosis is defined as a morphologically distinct form of programmed cell death[6] that is mediated by a number of proteases (called caspases) that cleave their target proteins at specific aspartate residues. Autophagyrelated proteins interact with activated caspases that hinder or reinforce autophagy[7]. Apoptosis or programmed cell death will occur in response to persistent activation of autophagy[9] Autophagy can increase the ability of tumour cells to overcome starvation and stress by preventing excessive protein degradation[8].

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Results

Conclusion