m6Am methyltransferase PCIF1 is essential for aggressiveness of gastric cancer cells by inhibiting TM9SF1 mRNA translation

Wei Zhuo; Meng Sun; Kun Wang; Lu Zhang; Kai Li; Danyang Yi; Mengjie Li; Qiang Sun; Xixi Ma; Wei Liu; Lisong Teng; Chengqi Yi; Tianhua Zhou

doi:10.1038/s41421-022-00395-1

m⁶Am methyltransferase PCIF1 is essential for aggressiveness of gastric cancer cells by inhibiting TM9SF1 mRNA translation

Cell Discov. 2022 May 21;8(1):48. doi: 10.1038/s41421-022-00395-1.

Authors

Wei Zhuo^#¹, Meng Sun^#², Kun Wang^#^{3

4}, Lu Zhang^#^{2

5}, Kai Li^{3

4}, Danyang Yi^{3

4}, Mengjie Li^{2

5}, Qiang Sun^{2

5}, Xixi Ma^{2

5}, Wei Liu², Lisong Teng⁶, Chengqi Yi^{7

8}, Tianhua Zhou^{9

10

11}

Affiliations

¹ Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. wzhuo@zju.edu.cn.
² Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
⁴ Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
⁵ Cancer Center, Zhejiang University, Hangzhou, China.
⁶ Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁷ State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. chengqi.yi@pku.edu.cn.
⁸ Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. chengqi.yi@pku.edu.cn.
⁹ Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. tzhou@zju.edu.cn.
¹⁰ Cancer Center, Zhejiang University, Hangzhou, China. tzhou@zju.edu.cn.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. tzhou@zju.edu.cn.

^# Contributed equally.

Abstract

PCIF1 (phosphorylated CTD interacting factor 1) is the first reported RNA N6,2'-O-dimethyladenosine (m⁶Am) methyltransferase. However, the pathological significance of PCIF1 and m⁶Am modification remains unknown. Here we find that both PCIF1 expression and m⁶Am modification are significantly elevated in gastric cancer tissues. Increased PCIF1 is associated with gastric cancer progression, and predicts poor prognosis. Silence of PCIF1 inhibits the proliferation and invasion of gastric cancer cells, and suppresses tumor growth and metastasis in mouse model. m⁶Am-seq analysis reveals TM9SF1 (transmembrane 9 superfamily member 1) as a target of PCIF1. PCIF1 modifies TM9SF1 mRNA with m⁶Am leading to decreased TM9SF1 translation. TM9SF1 reverses the effects of PCIF1 on gastric cancer cell aggressiveness. Collectively, our work uncovers an oncogenic function of PCIF1, providing insights into the critical role of m⁶Am modification in cancer progression.

Abstract

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