CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes

Yanfen Zheng, Xingyang Li, Shuang Deng, Hongzhe Zhao, Ying Ye, Shaoping Zhang, Xudong Huang, Ruihong Bai, Lisha Zhuang, Quanbo Zhou, Mei Li, Jiachun Su, Rui Li, Xiaoqiong Bao, Lingxing Zeng, Rufu Chen, Jian Zheng, Dongxin Lin (), Chuan He (), Jialiang Zhang () and Zhixiang Zuo ()
Additional contact information
Yanfen Zheng: Sun Yat-sen University Cancer Center
Xingyang Li: Sun Yat-sen University Cancer Center
Shuang Deng: Sun Yat-sen University Cancer Center
Hongzhe Zhao: Sun Yat-sen University Cancer Center
Ying Ye: Sun Yat-sen University Cancer Center
Shaoping Zhang: Sun Yat-sen University Cancer Center
Xudong Huang: Sun Yat-sen University Cancer Center
Ruihong Bai: Sun Yat-sen University Cancer Center
Lisha Zhuang: Sun Yat-sen University Cancer Center
Quanbo Zhou: Sun Yat-sen University
Mei Li: Sun Yat-sen University Cancer Center
Jiachun Su: Sun Yat-sen University Cancer Center
Rui Li: Sun Yat-sen University Cancer Center
Xiaoqiong Bao: Sun Yat-sen University Cancer Center
Lingxing Zeng: Sun Yat-sen University Cancer Center
Rufu Chen: Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences
Jian Zheng: Sun Yat-sen University Cancer Center
Dongxin Lin: Sun Yat-sen University Cancer Center
Chuan He: The University of Chicago
Jialiang Zhang: Sun Yat-sen University Cancer Center
Zhixiang Zuo: Sun Yat-sen University Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract N6-methyladenosine (m6A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m6A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m6A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m6A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m6A regulator CSTF2 that co-transcriptionally regulates m6A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m6As have positive effects on the RNA level of host genes, and CSTF2-regulated m6As are mainly recognized by IGF2BP2, an m6A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.

Date: 2023
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DOI: 10.1038/s41467-023-41861-y

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