N6-methyladenosine modified LINC00901 promotes pancreatic cancer progression through IGF2BP2/MYC axis

Wan-Xin Peng; Fei Liu; Jia-Hong Jiang; Hang Yuan; Ziqiang Zhang; Liu Yang; Yin-Yuan Mo

doi:10.1016/j.gendis.2022.02.014

N6-methyladenosine modified LINC00901 promotes pancreatic cancer progression through IGF2BP2/MYC axis

Genes Dis. 2022 Mar 26;10(2):554-567. doi: 10.1016/j.gendis.2022.02.014. eCollection 2023 Mar.

Authors

Wan-Xin Peng^{1

2}, Fei Liu³, Jia-Hong Jiang⁴, Hang Yuan⁵, Ziqiang Zhang⁶, Liu Yang⁷, Yin-Yuan Mo^{2

8}

Affiliations

¹ Department of Surgical Oncology, The Children's Hospital, Zhejiang University School of Medicine, National Research Center for Child Health, Hangzhou, Zhejiang 310052, China.
² Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³ Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Research Center for Child Health, Hangzhou, Zhejiang 310052, China.
⁴ Department of Medical Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
⁵ Department of Colorectal Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
⁶ Department of Pulmonary Medicine, Tongji Hospital, Tongji University, Shanghai 200065, China.
⁷ Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
⁸ Department of Pharmacology/Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Abstract

Accumulating evidence indicates that RNA methylation at N⁶-methyladenosine (m6A) plays an important regulatory role in gene expression and aberrant mRNA m6A modification is often associated with a variety of cancers. However, little is known whether and how m6A-modification impacts long non-coding RNA (lncRNA) and lncRNA-mediated tumorigenesis, particularly in pancreatic ductal adenocarcinoma (PDAC). In the present study, we report that a previously uncharacterized lncRNA, LINC00901, promotes pancreatic cancer cell growth and invasion and moreover, LINC00901 is subject to m6A modification which regulates its expression. In this regard, YTHDF1 serves as a reader for the m6A modified LINC00901 and downregulates the LINC00901 level. Notably, two conserved m6A sites in LINC00901 are critical to the recognition of LINC00901 by YTHDF1. Finally, RNA sequencing (RNA-seq) and gene function analysis revealed that LINC00901 positively regulates MYC through upregulation of IGF2BP2, a known RNA binding protein that can enhance MYC mRNA stability. Together, our results suggest that there is a LINC00901-IGF2BP2-MYC axis through which LINC00901 promotes PDAC progression in an m6A dependent manner.

Keywords: IGF2BP2; LINC00901; MYC; N6-methyladenosine modification (m6A); PDAC; YTHDF1.