Peng Wan-Xin, Liu Fei, Jiang Jia-Hong, Yuan Hang, Zhang Ziqiang, Yang Liu, Mo Yin-Yuan
Department of Surgical Oncology, The Children's Hospital, Zhejiang University School of Medicine, National Research Center for Child Health, Hangzhou, Zhejiang 310052, China.
Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Genes Dis. 2022 Mar 26;10(2):554-567. doi: 10.1016/j.gendis.2022.02.014. eCollection 2023 Mar.
Accumulating evidence indicates that RNA methylation at N-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.
越来越多的证据表明,N6-甲基腺苷(m6A)处的RNA甲基化在基因表达中起重要调节作用,而异常的mRNA m6A修饰通常与多种癌症相关。然而,关于m6A修饰是否以及如何影响长链非编码RNA(lncRNA)和lncRNA介导的肿瘤发生,尤其是在胰腺导管腺癌(PDAC)中,人们知之甚少。在本研究中,我们报告了一种以前未被表征的lncRNA,即LINC00901,它促进胰腺癌细胞的生长和侵袭,此外,LINC00901受到m6A修饰的调控,从而调节其表达。在这方面,YTHDF1作为m6A修饰的LINC00901的读取器,并下调LINC00901的水平。值得注意的是,LINC00901中的两个保守m6A位点对于YTHDF1识别LINC00901至关重要。最后,RNA测序(RNA-seq)和基因功能分析表明,LINC00901通过上调IGF2BP2来正向调节MYC,IGF2BP2是一种已知的RNA结合蛋白,可以增强MYC mRNA的稳定性。总之,我们的结果表明存在一个LINC00901-IGF2BP2-MYC轴,通过该轴LINC00901以m6A依赖的方式促进PDAC进展。