A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling

Jianong Zhang; Jiangbo Wei; Rui Sun; Haoyue Sheng; Kai Yin; Yunqian Pan; Rafael Jimenez; Sujun Chen; Xiao-Long Cui; Zhongyu Zou; Zhiying Yue; Michael J Emch; John R Hawse; Liguo Wang; Housheng Hansen He; Shujie Xia; Bangmin Han; Chuan He; Haojie Huang

doi:10.1016/j.molcel.2023.06.024

A lncRNA from the FTO locus acts as a suppressor of the m⁶A writer complex and p53 tumor suppression signaling

Mol Cell. 2023 Aug 3;83(15):2692-2708.e7. doi: 10.1016/j.molcel.2023.06.024. Epub 2023 Jul 20.

Authors

Jianong Zhang¹, Jiangbo Wei², Rui Sun³, Haoyue Sheng³, Kai Yin⁴, Yunqian Pan³, Rafael Jimenez⁵, Sujun Chen⁶, Xiao-Long Cui², Zhongyu Zou², Zhiying Yue⁷, Michael J Emch³, John R Hawse³, Liguo Wang⁸, Housheng Hansen He⁶, Shujie Xia⁹, Bangmin Han⁹, Chuan He¹⁰, Haojie Huang¹¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Hongkou District, Shanghai 200080, China. Electronic address: hugebox@qq.com.
² Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
³ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
⁴ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang 212002, China.
⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
⁷ Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
⁸ Department of Computation Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
⁹ Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Hongkou District, Shanghai 200080, China.
¹⁰ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
¹¹ Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: huang.haojie@mayo.edu.

PMID: 37478845
PMCID: PMC10427207 (available on 2024-08-03)
DOI: 10.1016/j.molcel.2023.06.024

Abstract

N⁶-methyladenosine (m⁶A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m⁶A demethylases such as FTO play important roles in regulating mRNA stability, splicing, and translation. Here, we demonstrate that FTO-IT1 long noncoding RNA (lncRNA) was upregulated and positively correlated with poor survival of patients with wild-type p53-expressing prostate cancer (PCa). m⁶A RIP-seq analysis revealed that FTO-IT1 knockout increased mRNA m⁶A methylation of a subset of p53 transcriptional target genes (e.g., FAS, TP53INP1, and SESN2) and induced PCa cell cycle arrest and apoptosis. We further showed that FTO-IT1 directly binds RBM15 and inhibits RBM15 binding, m⁶A methylation, and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restored mRNA m⁶A level and expression of p53 target genes and inhibited PCa growth in mice. Our study identifies FTO-IT1 lncRNA as a bona fide suppressor of the m⁶A methyltransferase complex and p53 tumor suppression signaling and nominates FTO-IT1 as a potential therapeutic target of cancer.

Keywords: FTO; FTO-IT1; METTL14; METTL3; N(6)-methyladenosine; RBM15; lncRNA; m(6)A; p53; prostate cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adenosine / metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
Animals
Male
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Neoplasms*
RNA, Long Noncoding* / genetics
RNA, Messenger / genetics
Tumor Suppressor Protein p53 / genetics

Substances

RNA, Long Noncoding
Tumor Suppressor Protein p53
Adenosine
RNA, Messenger
Methyltransferases
FTO protein, mouse
Alpha-Ketoglutarate-Dependent Dioxygenase FTO

Abstract

Publication types

MeSH terms

Substances

Grants and funding