FTO downregulation mediated by hypoxia facilitates colorectal cancer metastasis

Dan-Yun Ruan,Yang Li,Ting Li,Min Wang,Qi Zhao,Qi Meng,Ze-Xian Liu,Rui-Hua Xu,Long Bai,Li-Zhi Luo,De-Shen Wang,Jun-Zhong Lin,Ying-Nan Wang,Jin-Fei Lin,Xiang-Yuan Wu,Huai-Qiang Ju,Kai Yu

doi:10.1038/s41388-021-01916-0

Abstract

Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, participates in tumor progression and metastasis in many malignancies, but its role in colorectal cancer (CRC) is still unclear. Here, we found that FTO protein levels, but not RNA levels, were downregulated in CRC tissues. Reduced FTO protein expression was correlated with a high recurrence rate and poor prognosis in resectable CRC patients. Moreover, we demonstrated that hypoxia restrained FTO protein expression, mainly due to an increase in ubiquitin-mediated protein degradation. The serine/threonine kinase receptor associated protein (STRAP) might served as the E3 ligase and K216 was the major ubiquitination site responsible for hypoxia-induced FTO degradation. FTO inhibited CRC metastasis both in vitro and in vivo. Mechanistically, FTO exerted a tumor suppressive role by inhibiting metastasis-associated protein 1 (MTA1) expression in an m6A-dependent manner. Methylated MTA1 transcripts were recognized by an m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which then stabilized its mRNA. Together, our findings highlight the critical role of FTO in CRC metastasis and reveal a novel epigenetic mechanism by which the hypoxic tumor microenvironment promotes CRC metastasis.

Highlights

Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the second leading cause of cancer death worldwide [1]
We previously revealed the oncogenic role of the m6A writer methyltransferase like 3 (METTL3) in CRC [13], and we speculated that erasers might be involved in the progression of CRC
We found that fat mass- and obesity-associated protein (FTO) was downregulated at the protein level but not at the mRNA level in CRC tumor tissues, while AlkB homolog 5 (ALKBH5) expression did not show any differences (Fig. 1A, B, Supplementary Information: Fig. S1A)

Summary

Introduction

Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the second leading cause of cancer death worldwide [1]. M6A modification is involved in cancer pathogenesis and progression through the m6A enzyme system, which is mainly composed of methyltransferases (“writers”), demethylases (“erasers”) and binding proteins (“readers”) [5, 7]. These m6A enzymes participate in the development of cancers, such as gliomas, leukemia, and breast cancer, by affecting different stages of the RNA life cycle, including pre-mRNA splicing, export, translation, and stability [8,9,10,11,12]. The role of FTO in CRC as an m6A demethylase remains poorly understood

Methods

Results

Conclusion